Azole compound and medicinal use thereof

ABSTRACT

The present invention relates to an azole compound represented by the formula [I]  
                 
 
wherein W is S or O; R is —COOR 7 , —X 1 -A 1 -COOR 7  (R 7  is H, alkyl) or tetrazolyl; R 1 , R 2 , R 3  and R 4  are H and the like; A is —(CH 2 ) m —X— (X is —N(R 8 )—, —C(R 9 )(R 10 )—, —CO— or —CO—N(R 8 )—); B is aryl or aromatic heterocyclic group; R 5  is H and the like; R 6  is —(Y) s1 -(A 2 ) s -Z (Y is —O—, —S(O) t —, —N(R 13 )—, —N(R 14 )—CO—, —N(R 14 )—SO 2 —, —SO 2 —N(R 14 )— and the like, A 2  is alkylene, and Z is cycloalkyl, aryl, aromatic heterocyclic group, indanyl, piperazinyl, a prodrug thereof or a pharmaceutically acceptable salt thereof. The compound [I] of the present invention has a protein tyrosine phosphatase 1B inhibitory activity, and is useful as a therapeutic agent for diabetes, a therapeutic drug for diabetic complications or a therapeutic drug for hyperlipidemia.

TECHNICAL FIELD

The present invention relates to a novel azole compound, moreparticularly, the present invention relates to an azole compound or apharmaceutically acceptable salt thereof having a protein tyrosinephosphatase 1B (PTP1B) inhibitory activity, and a pharmaceuticalcomposition containing the same.

BACKGROUND ART

Diabetes causes various metabolic abnormalities including a chronichyperglycemia state as a main characteristic, which shows varioussymptoms based on mouth dryness, polydipsia, polyuria, decrease in bodyweight and the like, based on hyperglycemia. It is known that, when suchhyperglycemia state is maintained for a long time, various complicationssuch as retinopathy, nephropathy, neuropathy, cardiac infarction andcerebral infarction based on arteriosclerosis, and the like aredeveloped.

Diabetes is roughly divided into four types of type I diabetes (IDDM;Insulin Dependent Diabetes Mellitus), wherein pancreatic beta cells aredamaged or destroyed to cause absolute insulin deficiency, type IIdiabetes (NIDDM; Non-Insulin Dependent Diabetes Mellitus) whereinrelative insulin deficiency is developed due to insulin resistance andlower insulin secretion, specific diabetes which secondarily resultsfrom genetic abnormalities, other diseases and the like, and gestationaldiabetes. Some of those diagnosed with type II diabetes at the time ofthe onset may gradually lose their ability to secrete insulin with theprogression of the disease and result in type I diabetes.

Considering the saccharometabolism of living organisms, energy sourcesand materials to be the constituent components of living organisms aretaken into the body intermittently; for example, the brain keeps onconsuming glucose. Under such situation, the blood glucose level ismaintained almost constantly, and what enables such control of the bloodglucose level includes hormones involved in control of the blood glucoselevel, metabolism in organs, interaction of exchanging sugar and thelike between organs. Of such hormones, particularly the action ofinsulin involved in the control of the blood glucose level is important,and its disorder, namely, insulin resistance and lower secretion ofinsulin are considered to be deeply involved in diabetes.

Insulin is secreted from pancreatic beta cells, binds with an insulinreceptor present on the membrane surface of the skeletal muscle cell andadipocyte, which are its target cells, after which tyrosine residue inthe intracellular domain is self-phosphorylated. Then, tyrosine residuessuch as insulin receptor substrate (IRS), APS (adapter proteincontaining PH and SH2 domain) and the like are phosphorylated and PI₃kinase -Akt pathway is activated, which causes translocation of glucosetransporter to cell membrane, where glucose uptake occurs to lower theblood glucose level. On the other hand, tyrosine phosphatase that causestyrosine dephosphorylation to negatively control intracellular signaltransduction by insulin is also present, and suppresses activationthereof. In this way, while tyrosine phosphorylation plays a key role inthe insulin action, considering that tyrosine phosphorylation depends onthe activity balance between tyrosine kinase (phosphorylation enzyme)and tyrosine phosphatase (dephosphorylation enzyme), tyrosinephosphatase is presumed to have function to significantly controlinsulin signal transduction directly together with tyrosine kinase.

At present, tyrosine phosphatase forms a large gene family and more than70 some kinds of isozyme have been reported. Of such isozymes, proteintyrosine phosphatase 1B (PTP1B) is considered to be a phosphatasespecific to insulin signal transduction. Particularly, given the reportson increased gene expression of PTP1B by high glucose culture, and shiftof intracellular localization thereof, which decreases insulin receptorand IRS-1 tyrosine phosphorylation and induces insulin resistance (J.Biol. Chem., 270: 7724-7730, 1995; J. Biochem. (Tokyo), 123: 813-820,1998); and introduction of wild-type PTP1B prevents translocation ofglucose transporter GLUT4, resulting in ineffectiveness in a phosphataseactivity deficient mutant, and recently on enhanced insulin sensitivityof PTP1B knockout mouse to be obesity resistant to high-fat diet(Science, 283: 1544-1548, 1999), this enzyme is suggested to be onepossible target of insulin resistance improvement. In fact, an insulinresistance improvement effect of vanadic acid long known as a tyrosinephosphatase inhibitor has been acknowledged in animal test and the like.

Accordingly, such tyrosine phosphatase, particularly a drug thatsuppresses and/or inhibits abnormal activation of PTP1B can be a newtype of therapeutic agent for diabetes, which enhances insulinsensitivity, insulin resistance and/or glucose resistance, and restoresnormal insulin intracellular signal transduction. In addition,application to a therapeutic drug for various diseases such as obesity,neurodegenerative disease and the like is also expected.

Recently, various reports have been documented on compounds aiming attreatment of diseases such as diabetes and the like, by inhibitingprotein tyrosine phosphatase.

For example, WO 00/17211 discloses a phosphonic acid derivative having aPTP1B inhibitory action. However, this publication does not disclose acompound having a structure as that of the compound of the presentinvention, not to mention a description suggestive thereof.

JP-11-508919A (U.S. Pat. No. 5,770,620) discloses an arylacrylic acidderivative useful as a protein tyrosine phosphatase inhibitor. However,this publication does not disclose a compound having a structure as thatof the compound of the present invention, not to mention a descriptionsuggestive thereof.

WO 98/27092 (U.S. Pat. No. 6,080,772) discloses a thiazole compoundhaving a protein tyrosine phosphatase inhibitory action. However, thispublication does not disclose a compound having a structure as that ofthe compound of the present invention, not to mention a descriptionsuggestive thereof.

WO 99/58522 discloses a naphtho[2,3-B]heteroal-4-yl derivative, WO99/58511 discloses an oxa/thiazole-aryl-carboxylic acid derivative, WO99/58521 and U.S. Pat. No. 6,110,962 disclose11-aryl-benzo[B]naphtho[2,3-D]furan and11-aryl-benzo[B]naphtho[2,3-D]thiophene derivatives, WO 99/58518discloses a biphenyl-oxo-acetic acid derivative, WO 99/61419 discloses a2,3,5-substituted biphenyl derivative, WO 99/58520 discloses abiphenyl-sulfonyl-aryl-carboxylic acid derivative, WO 99/61435 disclosesbenzothiophene, benzofuran and indole derivatives, U.S. Pat. No.6,103,708 discloses furan, benzofuran and thiophene derivatives, U.S.Pat. No. 6,110,963 discloses an aryl-oxo-acetic acid derivative, U.S.Pat. No. 6,001,867 discloses a 1-aryl-dibenzothiophene derivative, U.S.Pat. No. 6,057,316 discloses a 4-aryl-1-oxa-9-thia-cyclopenta[B]fluorenederivative, U.S. Pat. No. 6,063,815 discloses a benzophenone derivative,as each having a protein tyrosine phosphatase inhibitory action.However, these publications do not disclose compounds having a structureas that of the compound of the present invention, not to mention adescription suggestive thereof.

As compounds having a thiazole or oxazole structure, the following havebeen reported.

WO 00/45635 discloses a 2-substituted thiazole derivative. However, thecompound of this publication has a carbamoyl group at the terminal ofthe substituent at the 2-position of the thiazole ring and thispublication does not disclose a compound having a structure as that ofthe compound of the present invention, not to mention a descriptionsuggestive thereof. In addition, the compound of this publication isuseful as an antimicrobial agent or an analgesic, and the publicationdoes not disclose its usefulness as a PTP1B inhibitor, not to mention adescription suggestive thereof.

JP-2000-504039A describes a 2-anilino-4-phenylthiazole derivative.However, the compound of this publication has an anilino groupsubstituted by a hydroxyl group or a carboxyl group at the 2-position ofa thiazole ring, a phenyl group at the 4-position, and a substituent atthe 2-position of the 4-position phenyl group, and this publication doesnot disclose a compound having a structure as that of the compound ofthe present invention, not to mention a description suggestive thereof.In addition, the compound of this publication is useful as a CRF(corticotropin releasing factor) antagonist, and the publication doesnot disclose its usefulness as a PTP1B inhibitor, not to mention adescription suggestive thereof.

JP-A-4-154773 describes a thiazole derivative represented by the formula

wherein R¹ and R² are the same or different and each is hydrogen atom,halogen atom, lower alkyl group, phenyl group, substituted phenyl group,pyridyl group or substituted pyridyl group, R³ is hydroxyl group, loweralkoxy group or —N(R⁵)(R⁶) wherein R⁵ and R⁶ are the same or differentand each is hydrogen atom or lower alkyl group, R⁴ is hydrogen atom orlower alkyl group, and X is amino group, amide group, carbonyl group,alkylene group, oxygen atom or sulfur atom. However, this publicationdoes not disclose a compound having a structure as that of the compoundof the present invention, not to mention a description suggestivethereof. In addition, the compound of this publication is useful as anantiinflammatory agent, and the publication does not disclose itsusefulness as a PTP1B inhibitor, not to mention a description suggestivethereof.

WO 94/08982 describes a 4-phenylthiazole derivative. However, thecompound of this publication has phenyl group at the 4-position of athiazole ring, and a substituent such as halogen and the like at the2-position of the 4-position phenyl group. This publication does notdisclose a compound having a structure as that of the compound of thepresent invention, not to mention a description suggestive thereof. Inaddition, the compound of this publication is useful as a pest controlagent, and the publication does not disclose its usefulness as a PTP1Binhibitor, not to mention a description suggestive thereof.

WO 02/39997 describes compounds represented by the formula

wherein R⁶ is hydroxyl group or protected prodrug moiety, R⁷ is hydrogenatom, carboxy group, arylaminocarbonyl group, aroyl group, aryl group,alkylaminocarbonyl group, aminocarbonyl group, alkenylaminocarboxygroup, hydroxyl group, alkoxy group, ether, thiol, aminogroup-containing heterocyclic group or protected prodrug moiety, R⁸ ishydrogen atom or alkyl group that may be bonded with D to form a ring,R⁹ is lower alkyl group or hydrogen atom, Q is bond, oxygen atom, sulfuratom, CR³OH, CR³ SH, CR³NR^(3a)R^(3b), NR³, (CR³R^(3a))_(n),O(CR³R^(3b))_(n) or (CR³R^(3a))_(n)O(CR^(3b)R^(3c))_(n) wherein n is aninteger of 0 or 1 to 3, R³, R^(3a), R^(3b) and R^(3c) are eachindependently hydrogen atom, optionally substituted straight chain,cyclic or branched chain C₁₋₆ alkyl group, C₂₋₆ alkenyl group, acylgroup, arylalkyl group, aryloxycarbonyl group, arylaminocarbonyl group,arylalkylsulfonyl group or aryl group, G is a linking moiety, M isanchor moiety, J is bond, alkylene group, alkenylene group or alkynylenegroup, D is hydrogen atom, alkoxy group, amine, alkyl group, alkenylgroup, alkynyl group, aryl group or heteroaryl group that may be bondedwith G, M or Q to form a ring, t is 0 or 1, p is 0 or an integer of 1 to5, and q is 0 or an integer of 1 to 3, andthe formula

wherein P⁴ is carboxy group, cleavable prodrug moiety, COOP^(4′),(CH₂)₁₋₄SP^(4′) or C(O)NP^(4′)P^(4″), R⁷ is hydrogen atom, carboxygroup, optionally substituted lower alkyl ester, lower alkenyl ester,ester added with secondary amine substituted by lower alkyl,arylaminocarbonyl group, aroyl group, aryl group, alkylaminocarbonylgroup, aminocarbonyl group, COOR^(7′), CONR^(7′)R^(7″), hydroxyl group,ether, thiol, amino group, (CH₂)₁₋₄SR^(7′), heterocyclic group orcleavable prodrug moiety, P^(4′), P^(4″) R^(7′) and R^(7″) are eachindependently hydrogen atom, C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆alkynyl group or optionally substituted aryl group, R⁸ is hydrogen atom,alkyl group or covalent bond with D, R⁹ is lower alkyl group or hydrogenatom, Q is bond, oxygen atom, sulfur atom, CR³OH, CR³SH,CR³NR^(3a)R^(3b), NR³, (CR³R^(3a)), O(CR³R^(3b))_(n) or(CR³R^(3a))_(n)O(CR^(3b)R^(3c))_(n) wherein n is 0 or an integer of 1 to3, R³, R^(3a), R^(3b) and R^(3c) are each independently hydrogen atom,optionally substituted C₁₋₆ straight chain or branched chain alkylgroup, C₂₋₆ straight chain or branched chain alkenyl group,aryloxycarbonyl group, arylaminocarbonyl group, arylalkylsulfonyl group,arylalkyl group, optionally substituted acyl group, aryl group or C₃₋₈ring optionally substituted by up to 4 hetero atoms, P^(2a), P^(2b),P^(3a) and P^(3b) are each independently hydrogen atom or optionallysubstituted straight chain, branched chain or cyclic C₁₋₅ alkyl group, Gis linking moiety, M is anchor moiety, J is bond, alkylene group,alkenylene group or alkynylene group, D is hydrogen atom, alkyl group,alkenyl group, alkynyl group or aryl group or may be bonded with G, M orQ to form a ring, t is 0 or 1, p is 0 or an integer of 1 to 5, and q is0 or an integer of 1 to 3, wherein the anchor moiety in each formula isexemplified by thiazole group and oxazole group having, as asubstituent, aryl group or heteroaryl group substituted by —NR′R″,—CONR′R″, —S(O)₂NR′R″, —S(O)₀₋₂R′, —NR′R″, —O(CR′R″)₀₋₂CF₃, —COR′,—CO₂R′ and —OR′ wherein R′ and R″ are each independently hydrogen atom,C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group or optionallysubstituted aryl group, and the linking moiety is exemplified bycovalent bond and C₁₋₆ alkyl group.

Moreover, a compound represented by the formula

wherein M is carbocyclic group, heterocyclic group or CONR′R″ wherein R′and R″ are each independently hydrogen atom, C₁₋₆ alkyl group, C₂₋₆alkenyl group, C₂₋₆ alkynyl group or optionally substituted aryl group,Q is bond, oxygen atom, sulfur atom, CR³OH, CR³SH, CR³NR^(3a)R^(3b),NR³, (CR³R^(3a))_(n), O(CR³R^(3b)) or(CR³R^(3a))_(n)O(CR^(3b)R^(3c))_(n) wherein n is 0 or an integer of 1 to3, R³, R^(3a)R^(3b) and R^(3c) are each independently hydrogen atom,optionally substituted branched chain, cyclic or straight chain C₁₋₆alkyl group, C₂₋₆ alkenyl group, acyl group, arylalkyl group,aryloxycarbonyl group, arylaminocarbonyl group, arylalkylsulfonyl groupor aryl group, K is independently selected sublinking moiety, L isindependently selected subanchor moiety, P⁴ is hydrogen atom, carboxygroup, (CH₂)₁₄SP^(4′), cleavable prodrug moiety, COOP^(4′) orCONP^(4′)P^(4″), R⁷ is hydrogen atom, carboxy group, aroyl group, arylgroup, COOR⁷, C(O)NR^(7′)R^(7″), hydroxyl group, ether, thiol,(CH₂)₁₋₄SR^(7′), heterocyclic group or cleavable prodrug moiety, P⁴,P^(4″), R^(7′) and R^(7″) are each independently hydrogen atom, C₁₋₆alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group or optionallysubstituted aryl group, n is 0 or an integer of 1 to 4, D is hydrogenatom, alkyl group, alkoxy group, alkenyl group, amine, hydroxyl group,alkynyl group, aryl group or heteroaryl group, and t is 0 or 1, isdescribed, wherein the sublinking moiety has a covalent bond and thesubanchor moiety has an optionally substituted aryl group.

However, this publication does not disclose a compound having astructure as that of the compound of the present invention, not tomention a description suggestive thereof. In addition, the compound ofthis publication is useful as an angiotensin converting enzyme (ACE)-2regulator, and the publication does not disclose its usefulness as aPTP1B inhibitor, not to mention a description suggestive thereof.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a compound having asuperior PTP1B inhibitory action and useful as a therapeutic agent fordiabetes, a therapeutic agent for hyperlipidemia or a therapeutic drugof diseases such as obesity, neurodegenerative disease and the like.

Another object of the present invention is to provide a PTP1B inhibitor,a therapeutic agent for diabetes and a therapeutic agent forhyperlipidemia.

The present inventors have conducted intensive studies in an attempt toachieve the above-mentioned objects and found that an azole compoundrepresented by the following formula [I] has a superior PTP1B inhibitoryaction and is useful as a PTP1B inhibitor, a therapeutic agent fordiabetes and a therapeutic agent for hyperlipidemia, which resulted inthe completion of the present invention.

The present invention relates to the compounds shown in the following[1] to [54] and use thereof as a pharmaceutical agent.[1] An azole compound represented by the formula [I]

wherein

-   W is a sulfur atom or an oxygen atom;-   R is-   (1) —COOR⁷ wherein R⁷ is a hydrogen atom or a lower alkyl group),-   (2) —X¹-A¹-COOR⁷    wherein-   X¹ is —O—, —N(R¹⁵)— or —S(O)_(p)— wherein R¹⁵ is a hydrogen atom or    a lower alkyl group, p is 0, 1 or 2,-   A¹ is a lower alkylene group, and-   R⁷ is a hydrogen atom or a lower alkyl group, or-   (3) a tetrazolyl group;-   R¹, R², R³⁴ and R⁴ are each independently-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a hydroxyl group,-   (4) an optionally substituted lower cycloalkylalkyloxy group,-   (5) an optionally substituted aralkyloxy group,-   (6) a cyano group,-   (7) a nitro group,-   (8) a lower alkyl group,-   (9) a lower haloalkyl group,-   (10) a lower alkoxy group or-   (11) a lower haloalkoxy group;-   A is a group represented by —(CH₂)_(m)—X—    wherein-   X is —N(R⁸)—, —C(R⁹)(R¹⁰)—, —CO— or —CO—N(R⁸)—    wherein-   R⁸ is a hydrogen atom, —SO₂R¹⁶ (R¹⁶ is a lower alkyl group or an    aryl group) or a lower alkyl group, wherein said lower alkyl group    is optionally substituted by a substituent selected from the group    consisting of a lower alkoxy group, an aryloxy group, —N(R¹¹)(R¹²)    (R¹¹ and R¹² are each independently a hydrogen atom or a lower alkyl    group or may form, together with a nitrogen atom bonded thereto, a    5- to 7-membered hetero ring optionally further having at least one    hetero atom selected from the group consisting of nitrogen atom,    oxygen atom and sulfur atom), a carboxy group, a lower cycloalkyl    group and an optionally substituted aryl group, and-   R⁹ and R¹⁰ are each independently a hydrogen atom or a lower alkyl    group or may form lower cycloalkane together with a carbon atom    bonded thereto, or may form, together with a carbon atom bonded    thereto, a 5- to 7-membered hetero ring optionally further having at    least one hetero atom selected from the group consisting of nitrogen    atom, oxygen atom and sulfur atom, and-   m is 0 or an integer of 1 to 3;-   B is an aryl group or an aromatic heterocyclic group;-   R⁵ is-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a lower alkyl group,-   (4) a lower alkoxy group,-   (5) a cyano group,-   (6) a nitro group,-   (7) a lower haloalkyl group or-   (8) —S(O)_(r)—R¹⁷ (R¹⁷ is a lower alkyl group or an aryl group and r    is 0, 1 or 2); and-   R⁶ is —(Y)_(s1)-(A²)_(s)-Z    wherein-   s1 and s are each independently 0 or 1,-   Y is —O—, —S(O)_(t)—, —N(R¹³)—, —N(R¹⁴)—CO—, —N(R¹⁴)—SO₂—,    —SO₂——N(R¹⁴)—, —C(R⁸)(R¹⁹)— or —CO—    (wherein-   t is 0, 1 or 2,-   R¹³ is-   (1) a hydrogen atom,-   (2) a lower alkyl group    (wherein said lower alkyl group optionally substituted by a    substituent selected from the group consisting of    -   (a) a lower cycloalkyl group,    -   (b) an optionally substituted aryl group,    -   (c) an optionally substituted heterocyclic group and    -   (d) a hydroxyl group),-   (3) a lower alkenyl group,-   (4) a lower alkylsulfonyl group or-   (5) a lower alkylcarbonyl group    (wherein said lower alkylcarbonyl group is optionally substituted by    a hydroxyl group or a lower alkoxy group),-   R¹⁴ is a hydrogen atom or a lower alkyl group, and-   R¹⁸ and R¹⁹ are each independently a hydrogen atom or a lower alkyl    group or may form lower cycloalkane together with a carbon atom    bonded thereto, or may form, together with a carbon atom bonded    thereto, a 5- to 7-membered hetero ring optionally further having at    least one hetero atom selected from the group consisting of nitrogen    atom, oxygen atom and sulfur atom),-   A² is a lower alkylene group optionally substituted by a lower    cycloalkyl group, and-   Z is-   (1) a lower cycloalkyl group    (wherein said a lower cycloalkyl group is optionally substituted by    an optionally substituted phenyl group),-   (2) an aryl group    (wherein said aryl group is optionally substituted by a substituent    selected from the group consisting of    -   (a) a heterocyclic group optionally substituted by a substituent        selected from the group consisting of a lower alkyl group and a        lower alkylcarbonyl group,    -   (b) a lower cycloalkyl group optionally substituted by a        substituent selected from the group consisting of a hydroxyl        group, an oxo group, a halogen atom and a lower alkyl group,    -   (c) a carboxy group,    -   (d) a halogen atom,    -   (e) an alkyl group,    -   (f) a lower haloalkyl group,    -   (g) a lower alkylamino group,    -   (h) a di(lower alkyl)amino group,    -   (i) a lower alkylthio group and    -   (j) a lower alkoxy group),-   (3) an optionally substituted aromatic heterocyclic group,-   (4) an indanyl group or-   (5) a piperazinyl group    (wherein said piperazinyl group is optionally substituted by a    substituent selected from the group consisting of    -   (a) a phenyl group,    -   (b) a phenyl lower alkyl group,    -   (c) a benzoyl group optionally substituted by a halogen atom and    -   (d) a phenyl lower alkoxycarbonyl group),        a prodrug thereof or a pharmaceutically acceptable salt thereof.        [2] The azole compound of [1], wherein, in the formula [I],-   W is a sulfur atom or an oxygen atom;-   R is-   (1) —COOR⁷ wherein R⁷ is a hydrogen atom or a C₁₋₄ alkyl group,-   (2) —X¹-A¹-COOR⁷    wherein-   X¹ is —O—, —N(R¹⁵)— or —S(O)_(p)— wherein R¹⁵ is a hydrogen atom or    a C₁₋₄ alkyl group and p is 0, 1 or 2,-   A¹ is a C₁₋₄ alkylene group,-   R⁷ is a hydrogen atom or a C₁₋₄ alkyl group or-   (3) a tetrazolyl group,-   R¹, R², R³ and R⁴ are each independently,-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a hydroxyl group,-   (4) an optionally substituted C₃₋₇ cycloalkyl C₁₋₄ alkyloxy group,-   (5) an optionally substituted aralkyloxy group,-   (6) a cyano group,-   (7) a nitro group,-   (8) a C₁₋₄ alkyl group,-   (9) a C₁₋₄ haloalkyl group,-   (10) a C₁₋₄ alkoxy group or-   (11) a C₁₋₄ haloalkoxy group;-   A is a group represented by —(CH₂)_(m)—X—    wherein-   X is —N(R⁸)—, —C(R⁹)(R¹⁰)—, —CO— or —CO—N(R⁸)—    wherein-   R⁸ is a hydrogen atom, —SO₂R¹⁶ (R¹⁶ is a C₁₋₆ alkyl group or an aryl    group) or a C₁₋₆ alkyl group, wherein said C₁₋₆ alkyl group is    optionally substituted by a substituent selected from the group    consisting of a C₁₋₄ alkoxy group, an aryloxy group, —N(R¹¹)(R¹²)    (R¹¹ and R¹² are each independently a hydrogen atom or a C₁₋₄ alkyl    group or may form, together with a nitrogen atom bonded thereto, a    5- to 7-membered hetero ring optionally further having at least one    hetero atom selected from the group consisting of nitrogen atom,    oxygen atom and sulfur atom), a carboxy group, a C₃₋₇ cycloalkyl    group and an optionally substituted aryl group, R⁹ and R¹⁰ are each    independently a hydrogen atom or a C₁₋₄ alkyl group, or may form a    C₃₋₇ cycloalkane together with a carbon atom bonded thereto, or may    form, together with a carbon atom bonded thereto, a 5- to 7-membered    hetero ring optionally further having at least one hetero atom    selected from the group consisting of nitrogen atom, oxygen atom and    sulfur atom,-   m is 0 or an integer of 1 to 3;-   B is an aryl group or an aromatic heterocyclic group;-   R⁵ is-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₄ alkyl group,-   (4) a C₁₋₄ alkoxy group,-   (5) a cyano group,-   (6) a nitro group,-   (7) a C₁₋₄ haloalkyl group or-   (8) —S(O)_(r)—R¹⁷ (R¹⁷ is a C₁₋₆ alkyl group or an aryl group and-   r is 0, 1 or 2);-   R⁶ is —(Y)_(s1)-(A²)_(s)-Z    wherein-   s1 and s are each independently 0 or 1,-   Y is —O—, —S(O)_(t)—, —N(R¹³)—, —N(R¹⁴)—CO—, —N(R¹⁴)—SO₂—,    —SO₂—N(R¹⁴)—, —C(R¹)(R¹⁹)— or —CO—    (wherein-   t is 0, 1 or 2,-   R¹³ is-   (1) a hydrogen atom,-   (2) a C₁₋₄ alkyl group    (wherein said C₁₋₄ alkyl group is optionally substituted by a    substituent selected from the group consisting of    -   (a) a C₃₋₇ cycloalkyl group,    -   (b) an optionally substituted aryl group,    -   (c) an optionally substituted heterocyclic group and    -   (d) a hydroxyl group),-   (3) a C₂₋₄ alkenyl group,-   (4) a C₁₋₄ alkylsulfonyl group or-   (5) a C₁₋₄ alkylcarbonyl group    (wherein said C₁₋₄ alkylcarbonyl group is optionally substituted by    a hydroxyl group or a C₁₋₄ alkoxy group),-   R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group,-   R¹⁸ and R¹⁹ are each independently a hydrogen atom or a C₁₋₄ alkyl    group, or may form C₃₋₇ cycloalkane together with a carbon atom    bonded thereto, or may form, together with a carbon atom bonded    thereto, a 5- to 7-membered hetero ring optionally further having at    least one hetero atom selected from the group consisting of nitrogen    atom, oxygen atom and sulfur atom),-   A² is a C₁₋₄ alkylene group optionally substituted by a C₃₋₇    cycloalkyl group,-   Z is-   (1) a C₃₋₇ cycloalkyl group    (wherein said C₃₋₇ cycloalkyl group is optionally substituted by a    phenyl group optionally substituted by a halogen atom),-   (2) an aryl group    (wherein said aryl group is optionally substituted by a substituent    selected from the group consisting of    -   (a) a heterocyclic group optionally substituted by a substituent        selected from the group consisting of a C₁₋₄ alkyl group and a        C₁₋₄ alkylcarbonyl group,    -   (b) a C₃₋₇ cycloalkyl group optionally substituted by a        substituent selected from the group consisting of a hydroxyl        group, an oxo group, a halogen atom and a C₁₋₄ alkyl group,    -   (c) a carboxy group,    -   (d) a halogen atom,    -   (e) a C₁₋₈ alkyl group,    -   (f) a C₁₋₄ haloalkyl group,    -   (g) a C₁₋₄ alkylamino group,    -   (h) a di(C₁₋₄ alkyl)amino group,    -   (i) a C₁₋₄ alkylthio group and    -   (j) a C₁₋₄ alkoxy group),-   (3) an aromatic heterocyclic group    (wherein said aromatic heterocyclic group is optionally substituted    by a substituent selected from the group consisting of    -   (a) a heterocyclic group optionally substituted by a C₁₋₄ alkyl        group,    -   (b) a C₁₋₆ alkyl group,    -   (c) an aryl group optionally substituted by a halogen atom or a        C₁₋₄ haloalkyl group,    -   (d) a halogen atom,    -   (e) a C₁₋₄ haloalkyl group,    -   (f) a carboxy group,    -   (g) a C₃₋₇ cycloalkyl group and    -   (h) a C₁₋₄ alkoxy group),-   (4) an indanyl group or-   (5) a piperazinyl group    (wherein said piperazinyl group is optionally substituted by a    substituent selected from the group consisting of    -   (a) a phenyl group,    -   (b) a phenyl C₁₋₄ alkyl group,    -   (c) a benzoyl group optionally substituted by a halogen atom and    -   (d) a phenyl C₁₋₄ alkoxycarbonyl group),        a prodrug thereof or a pharmaceutically acceptable salt thereof.        [3] The azole compound of [2], wherein W is a sulfur atom or an        oxygen atom,-   R is-   (1) —COOR⁷ wherein R⁷ is a hydrogen atom,-   (2) —X¹-A¹-COOR⁷    wherein-   X¹ is —O—,-   A¹ is a C₁₋₄ alkylene group,-   R⁷ is a hydrogen atom or-   (3) a tetrazolyl group;-   R¹, R², R³ and R⁴ are each independently-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a hydroxyl group,-   (4) an optionally substituted C₃₋₇ cycloalkyl C₁₋₄ alkyloxy group or-   (5) an optionally substituted aralkyloxy group;-   A is a group represented by —(CH₂)_(m)—X—    wherein-   X is —N(R⁸)—, —C(R⁹)(R¹⁰)— or —CO—    wherein-   R⁸ is a hydrogen atom or a C₁₋₆ alkyl group, wherein said C₁₋₆ alkyl    group is optionally substituted by a substituent selected from the    group consisting of a C₁₋₄ alkoxy group, an aryloxy group,    —N(R¹¹)(R¹²) (R¹¹ and R¹² are each independently a hydrogen atom or    a C₁₋₄ alkyl group or may form, together with a nitrogen atom bonded    thereto, a 5- to 7-membered hetero ring optionally further having at    least one hetero atom selected from the group consisting of nitrogen    atom, oxygen atom and sulfur atom), a carboxy group, a C₃₋₇    cycloalkyl group and an optionally substituted aryl group,-   R⁹ and R¹⁰ are each independently a hydrogen atom or a C₁₋₄ alkyl    group, or may form C₃₋₇ cycloalkane together with a carbon atom    bonded thereto, or may form, together with a carbon atom bonded    thereto, a 5- to 7-membered hetero ring optionally further having at    least one hetero atom selected from the group consisting of nitrogen    atom, oxygen atom and sulfur atom,-   m is 0 or an integer of 1 to 3;-   B is an aryl group or an aromatic heterocyclic group;-   R⁵ is-   (1) a hydrogen atom,-   (2) a halogen atom,-   (3) a C₁₋₄ alkyl group or-   (4) a C₁₋₄ alkoxy group;-   R⁶ is —(Y)_(s1)-(A²)_(s)-Z    wherein-   s1 and s are each independently 0 or 1,-   Y is —O—, —S(O)_(t)—, —N(R¹³)—, —N(R¹⁴)—CO— or —N(R¹⁴)—SO₂—    wherein-   t is 0, 1 or 2,-   R¹³ is-   (1) a hydrogen atom,-   (2) a C₁₋₄ alkyl group    (wherein said C₁₋₄ alkyl group is optionally substituted by a    substituent selected from the group consisting of    -   (a) a C₃₋₇ cycloalkyl group,    -   (b) an optionally substituted aryl group,    -   (c) an optionally substituted heterocyclic group and    -   (d) a hydroxyl group),-   (3) a C₂₋₄ alkenyl group,-   (4) a C₁₋₄ alkylsulfonyl group or-   (5) a C₁₋₄ alkylcarbonyl group    (wherein said C₁₋₄ alkylcarbonyl group is optionally substituted by    a hydroxyl group or a C₁₋₄ alkoxy group),-   R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group,-   A² is a C₁₋₄ alkylene group optionally substituted by a C₃₋₇    cycloalkyl group,-   Z is-   (1) a C₃₋₇ cycloalkyl group    (wherein said C₃₋₇ cycloalkyl group is optionally substituted by a    phenyl group),-   (2) an aryl group    (wherein said aryl group is optionally substituted by a substituent    selected from the group consisting of    -   (a) a heterocyclic group optionally substituted by a C₁₋₄ alkyl        group or a C₁₋₄ alkylcarbonyl group,    -   (b) a C₃₋₇ cycloalkyl group optionally substituted by a        substituent selected from the group consisting of a hydroxyl        group, an oxo group, a halogen atom and a C₁₋₄ alkyl group,    -   (c) a carboxy group,    -   (d) a halogen atom,    -   (e) a C₁₋₈ alkyl group,    -   (f) a C₁₋₄ haloalkyl group,    -   (g) a C₁₋₄ alkylamino group and    -   (h) a di(C₁₋₄ alkyl)amino group,    -   (i) a C₁₋₄ alkylthio group and    -   (j) a C₁₋₄ alkoxy group),-   (3) an aromatic heterocyclic group    (wherein said aromatic heterocyclic group is optionally substituted    by a substituent selected from the group consisting of    -   (a) a heterocyclic group,    -   (b) a C₁₋₄ alkyl group and    -   (c) a phenyl group optionally substituted by a halogen atom or a        C₁₋₄ haloalkyl group),-   (4) an indanyl group or-   (5) a piperazinyl group    (wherein said piperazinyl group is optionally substituted by a    substituent selected from the group consisting of    -   (a) a phenyl group,    -   (b) a phenyl C₁₋₄ alkyl group and    -   (c) a phenyl C₁₋₄ alkoxycarbonyl group),        a prodrug thereof or a pharmaceutically acceptable salt thereof.        [4] The azole compound of [3], wherein W is a sulfur atom and m        is 0 or 1, a prodrug thereof or a pharmaceutically acceptable        salt thereof.        [5] The azole compound of [4], wherein A is —(CH₂)_(m)—X—        wherein-   X is —N(R⁸)— wherein R⁸ is a hydrogen atom or a C₁₋₆ alkyl group,    wherein said C₁₋₆ alkyl group is optionally substituted by a    substituent selected from the group consisting of a C₁₋₄ alkoxy    group, an aryloxy group, —N(R¹¹)(R¹²) (R¹¹ and R¹² are each    independently a hydrogen atom or a C₁₋₄ alkyl group or may form,    together with a nitrogen atom bonded thereto, a 5- to 7-membered    hetero ring optionally further having at least one hetero atom    selected from the group consisting of nitrogen atom, oxygen atom and    sulfur atom), a carboxy group, a C₃₋₇ cycloalkyl group and an    optionally substituted aryl group, and-   m is 0 or 1,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [6] The azole compound of [5], wherein R is —X¹-A¹-COOR⁷    wherein each symbol is as defined in [3],    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [7] The azole compound of [5], wherein R is —COOR⁷ wherein-   R⁷ is a hydrogen atom,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [8] The azole compound of [7], wherein R¹, R², R³ and R⁴ are    hydrogen atoms,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [9] The azole compound of [8], wherein B is a phenyl group, a    thiazolyl group, a pyridyl group, a benzothiazolyl group, a    benzoimidazolyl group or a benzoxazolyl group,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [10] The azole compound of [9], wherein B is a phenyl group,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [11] The azole compound of [10], wherein R⁵ is a hydrogen atom,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [12] The azole compound of [11], wherein, for R⁶, Z is-   (1) a C₃₋₇ cycloalkyl group    (wherein said C₃₋₇ cycloalkyl group is optionally substituted by a    phenyl group),-   (2) an aryl group    (wherein said aryl group is optionally substituted by a substituent    selected from the group consisting of    -   (a) a heterocyclic group optionally substituted by a C₁₋₄ alkyl        group or a C₁₋₄ alkylcarbonyl group,    -   (b) a C₃₋₇ cycloalkyl group optionally substituted by a        substituent selected from the group consisting of a hydroxyl        group, an oxo group, a halogen atom and a C₁₋₄ alkyl group,    -   (c) a carboxy group,    -   (d) a halogen atom,    -   (e) a C₁₋₈ alkyl group,    -   (f) a C₁₋₄ haloalkyl group,    -   (g) a C₁₋₄ alkylamino group,    -   (h) a di(C₁₋₄ alkyl)amino group,    -   (i) a C₁₋₄ alkylthio group and    -   (j) a C₁₋₄ alkoxy group) or-   (3) an aromatic heterocyclic group    (wherein said aromatic heterocyclic group is optionally substituted    by a substituent selected from the group consisting of    -   (a) a heterocyclic group,    -   (b) a C₁₋₄ alkyl group and    -   (c) a phenyl group optionally substituted by a halogen atom or a        C₁₋₄ haloalkyl group),        a prodrug thereof or a pharmaceutically acceptable salt thereof.        [13] The azole compound of [12], wherein Z is an aryl group        optionally substituted by a substituent selected from the group        consisting of-   (a) a heterocyclic group optionally substituted by a C₁₋₄ alkyl    group or a C₁₋₄ alkylcarbonyl group,-   (b) a C₃₋₇ cycloalkyl group optionally substituted by a substituent    selected from the group consisting of a hydroxyl group, an oxo    group, a halogen atom and a C₁₋₄ alkyl group,-   (c) a carboxy group,-   (d) a halogen atom,-   (e) a C₁₋₈ alkyl group,-   (f) a C₁₋₄ haloalkyl group,-   (g) a C₁₋₄ alkylamino group,-   (h) a di(C₁₋₄ alkyl)amino group,-   (i) a C₁₋₄ alkylthio group and-   (j) a C₁₋₄ alkoxy group,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [14] The azole compound of [13], wherein Z is a phenyl group    substituted by a substituent selected from the group consisting of-   (a) a cyclohexyl group or a cyclopentyl group optionally substituted    by a substituent selected from the group consisting of a hydroxyl    group, an oxo group, a halogen atom and a C₁₋₄ alkyl group,-   (b) a heterocyclic group optionally substituted by a C₁₋₄ alkyl    group or a C₁₋₄ alkylcarbonyl group (wherein said heterocyclic group    is selected from the group consisting of a piperidinyl group, a    morpholinyl group, a piperazinyl group, a tetrahydropyranyl group, a    pyrrolidinyl group and a pyrrolyl group) and-   (c) a C₁₋₈ alkyl group,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [15] The azole compound of [14], wherein Z is a phenyl group    substituted by a cyclohexyl group optionally substituted by a    substituent selected from the group consisting of a hydroxyl group,    an oxo group, a halogen atom and a C₁₋₄ alkyl group,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [16] The azole compound of [13] or [14] wherein, for R⁶, Y is —O—,    —N(R¹³)— or —N(R¹⁴)—CO—    wherein-   R¹³ is a hydrogen atom, a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group,    wherein said C₁₋₄ alkyl group is optionally substituted by a    substituent selected from the group consisting of a C₃₋₇ cycloalkyl    group, an optionally substituted aryl group, an optionally    substituted heterocyclic group and a hydroxyl group,-   R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group, and s1 is 1,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [17] The azole compound of [16], wherein, for R⁶, A² is a methylene    group,    a prodrug thereof or a pharmaceutically acceptable salt thereof.    [18] A pharmaceutical composition comprising an azole compound of    any of [1] to [17], a prodrug thereof or a pharmaceutically    acceptable salt thereof, and a pharmaceutically acceptable carrier.    [19] A pharmaceutical composition for inhibiting protein Tyrosine    Phosphatase 1B, which comprises an azole compound of any of [1] to    [17], a prodrug thereof or a pharmaceutically acceptable salt    thereof, and a pharmaceutically acceptable carrier.    [20] A pharmaceutical composition for treating diabetes, which    comprises an azole compound of any of [1] to [17], a prodrug thereof    or a pharmaceutically acceptable salt thereof, and a    pharmaceutically acceptable carrier.    [21] A pharmaceutical composition for treating hyperlipidemia, which    comprises an azole compound of any of [1] to [17], a prodrug thereof    or a pharmaceutically acceptable salt thereof, and a    pharmaceutically acceptable carrier.    [22] The pharmaceutical composition of [18], which is used in    combination with a different therapeutic drug for hyperlipidemia.    [23] The pharmaceutical composition of [22], wherein the therapeutic    drug for hyperlipidemia is a statin pharmaceutical agent.    [24] The pharmaceutical composition of [23], wherein the statin    pharmaceutical agent is selected from the group consisting of    lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and    cerivastatin.    [25] The pharmaceutical composition of [18], which is used in    combination with a different therapeutic drug for diabetes.    [26] The pharmaceutical composition of [25], which is used in    combination with a therapeutic agent for diabetes selected from the    group consisting of an insulin secretagogue, a sulfonylurea, a    sulfonamide, a biguanide, an α glucosidase inhibitor, an insulin    preparation and an insulin sensitizer.    [27] The pharmaceutical composition of [26], wherein the therapeutic    agent for diabetes is selected from the group consisting of    nateglide, glimepiride, glibenclamide, gliclazide, acetohexamide,    tolbutamide, glyclopyramide, tolazamide, glybuzole, metformin    hydrochloride, buformin hydrochloride, voglibose, acarbose, insulin    and pioglitazone hydrochloride.    [28] The pharmaceutical composition of [20], which is used in    combination with a different therapeutic drug for hyperlipidemia.    [29] The pharmaceutical composition of [28], wherein the therapeutic    drug for hyperlipidemia is a statin pharmaceutical agent.    [30] The pharmaceutical composition of [29], wherein the statin    pharmaceutical agent is selected from the group consisting of    lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and    cerivastatin.    [31] The pharmaceutical composition of [20], which is used in    combination with a different therapeutic drug for diabetes.    [32] The pharmaceutical composition of [31], which is used in    combination with a therapeutic drug for diabetes selected from the    group consisting of an insulin secretagogue, a sulfonylurea, a    sulfonamide, a biguanide, an α glucosidase inhibitor, an insulin    preparation and an insulin sensitizer.    [33] The pharmaceutical composition of [32], wherein the therapeutic    agent for diabetes is selected from the group consisting of    nateglide, glimepiride, glibenclamide, gliclazide, acetohexamide,    tolbutamide, glyclopyramide, tolazamide, glybuzole, metformin    hydrochloride, buformin hydrochloride, voglibose, acarbose, insulin    and pioglitazone hydrochloride.    [34] The pharmaceutical composition of [21], which is used in    combination with a different therapeutic drug for hyperlipidemia.    [35] The pharmaceutical composition of [34], wherein the therapeutic    drug for hyperlipidemia is a statin pharmaceutical agent.    [36] The pharmaceutical composition of [35], wherein the statin    pharmaceutical agent is selected from the group consisting of    lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and    cerivastatin.    [37] The pharmaceutical composition of [21], which is used in    combination with a different therapeutic drug for diabetes.    [38] The pharmaceutical composition of [37], which is used in    combination with a therapeutic drug for diabetes selected from the    group consisting of an insulin secretagogue, a sulfonylurea, a    sulfonamide, a biguanide, an α glucosidase inhibitor, an insulin    preparation and an insulin sensitizer.    [39] The pharmaceutical composition of [38], wherein the therapeutic    agent for diabetes is selected from the group consisting of    nateglide, glimepiride, glibenclamide, gliclazide, acetohexamide,    tolbutamide, glyclopyramide, tolazamide, glybuzole, metformin    hydrochloride, buformin hydrochloride, voglibose, acarbose, insulin    and pioglitazone hydrochloride.    [40] A method of inhibiting protein Tyrosine Phosphatase 1B, which    comprises administering an effective amount of an azole compound of    any of [1] to [17], a prodrug thereof or a pharmaceutically    acceptable salt thereof to a mammal.    [41] A method of treating diabetes, which comprises administering an    effective amount of an azole compound of any of [1] to [17], a    prodrug thereof or a pharmaceutically acceptable salt thereof to a    mammal.    [42] A method of treating hyperlipidemia, which comprises    administering an effective amount of an azole compound of any of [1]    to [17], a prodrug thereof or a pharmaceutically acceptable salt    thereof to a mammal.    [43] Use of an azole compound of any of [1] to [17], a prodrug    thereof or a pharmaceutically acceptable salt thereof for the    production of a protein tyrosine phosphatase 1B inhibitor.    [44] Use of an azole compound of any of [1] to [17], a prodrug    thereof or a pharmaceutically acceptable salt thereof for the    production of a therapeutic agent for diabetes.    [45] Use of an azole compound of any of [1] to [17], a prodrug    thereof or a pharmaceutically acceptable salt thereof for the    production of a therapeutic agent for hyperlipidemia.    [46] A commercial package comprising the pharmaceutical composition    of [18] and a written matter associated therewith, the written    matter stating that said pharmaceutical composition can or should be    used for inhibiting protein Tyrosine Phosphatase 1B.    [47] A commercial package comprising the pharmaceutical composition    of [18] and a written matter associated therewith, the written    matter stating that said pharmaceutical composition can or should be    used for treating diabetes.    [48] A commercial package comprising the pharmaceutical composition    of [18] and a written matter associated therewith, the written    matter stating that said pharmaceutical composition can or should be    used for treating hyperlipidemia.    [49] A method of treating hyperlipidemia, which comprises    administering an effective amount of an azole compound of any of [1]    to [17], a prodrug thereof or a pharmaceutically acceptable salt    thereof to a mammal, and administering an effective amount of a    different therapeutic drug for hyperlipidemia to said mammal.    [50] The method of treating of [49], wherein the therapeutic drug    for hyperlipidemia is a statin pharmaceutical agent.    [51] The method of treating of [50], wherein the statin    pharmaceutical agent is selected from the group consisting of    lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and    cerivastatin.    [52] A method of treating diabetes, which comprises administering an    effective amount of an azole compound of any of [1] to [17], a    prodrug thereof or a pharmaceutically acceptable salt thereof to a    mammal, and administering an effective amount of a different    therapeutic agent for diabetes to said mammal.    [53] The method of treating of [52], wherein the therapeutic agent    for diabetes is selected from the group consisting of an insulin    secretagogue, a sulfonylurea, a sulfonamide, a biguanide, an α    glucosidase inhibitor, an insulin preparation and an insulin    sensitizer.    [54] The method of treating of [53], wherein the therapeutic agent    for diabetes is selected from the group consisting of nateglide,    glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide,    glyclopyramide, tolazamide, glybuzole, metformin hydrochloride,    buformin hydrochloride, voglibose, acarbose, insulin and    pioglitazone hydrochloride.

The definitions of respective substituents and respective moieties usedin the present specification are as follows.

In the present specification, “C₁₋₆” means that the carbon number is 1to 6.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atomor an iodine atom, with preference given to a fluorine atom and achlorine atom.

The “lower alkyl group” is a linear or branched chain alkyl group having1 to 6 carbon atoms, which is exemplified by methyl group, ethyl group,propyl group, isopropyl group, butyl group, isobutyl group, sec-butylgroup, tert-butyl group, pentyl group, isopentyl group, neopentyl group,tert-pentyl group, 1-ethylpropyl group and hexyl group. Preferred is alinear or branched chain alkyl group having 1 to 4 carbon atoms.

Preferably, it is a C₁₋₄ alkyl group for R¹, R², R³, R⁴, R⁵, R⁷, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁸ and R¹⁹, and a C₁₋₆ alkyl group forR⁸, R¹⁶ and R¹⁷.

The “lower haloalkyl group” is a haloalkyl group wherein a linear orbranched chain alkyl group having 1 to 6 carbon atoms is substituted bythe above-defined “halogen atom”, which is exemplified by fluoromethylgroup, difluoromethyl group, trifluoromethyl group, bromomethyl group,chloromethyl group, 1,2-dichloromethyl group, 2,2-dichloromethyl group,2,2,2-trifluoroethyl group and the like. Preferred is a linear orbranched chain haloalkyl group having 1 to 4 carbon atoms, andparticularly preferred is trifluoromethyl group.

Preferably, it is a C₁₋₄ haloalkyl group for R¹, R², R³, R⁴ and R⁵.

The “lower alkylene group” is a linear or branched chain alkylene grouphaving 1 to 6 carbon atoms, which is exemplified by methylene group,ethylene group, trimethylene group, propylene group, tetramethylenegroup, pentamethylene group, hexamethylene group and the like. Preferredis a linear or branched chain alkylene group having 1 to 4 carbon atomsand particularly preferred is methylene group.

Preferably, it is a C₁₋₄ alkylene group for A¹ and A².

The “lower alkoxy group” is a linear or branched chain alkoxy grouphaving 1 to 6 carbon atoms, which is exemplified by methoxy group,ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxygroup, tert-butoxy group, pentyloxy group, hexyloxy group and the like.Preferred is a linear or branched chain alkoxy group having 1 to 4carbon atoms.

Preferably, it is a C₁₋₄ alkoxy group for R¹, R², R³, R⁴ and R⁵.

The “lower haloalkoxy group” is a haloalkoxy group wherein a linear orbranched chain alkoxy group having 1 to 6 carbon atoms is substituted bythe above-defined “halogen atom”, which is exemplified byfluoromethyloxy group, difluoromethyloxy group, trifluoromethyloxygroup, bromomethyloxy group, chloromethyloxy group,1,2-dichloromethyloxy group, 2,2-dichloromethyloxy group,2,2,2-trifluoroethyloxy group and the like. Preferred is a linear orbranched chain haloalkoxy group having 1 to 4 carbon atoms, andparticularly preferred is a trifluoromethyloxy group.

Preferably, it is a C₁₋₄ haloalkoxy group for R¹, R², R³ and R⁴.

The “aryl group” is an aromatic hydrocarbon group having 6 to 14 carbonatoms, which is exemplified by phenyl group, naphthyl group, biphenylylgroup (e.g., 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl groupetc.), anthryl group and the like. Preferred are a phenyl group and abiphenylyl group, and more preferred is a phenyl group.

Preferably, it is a C₆₋₁₄ aryl group for R¹⁶, R¹⁷, B and Z.

The “aryloxy group” is an aryloxy group wherein the “aryl moiety” is theabove-defined “aryl group”, which is exemplified by phenoxy group,naphthyloxy group, biphenylyloxy group (e.g., 2-biphenylyloxy group,3-biphenylyloxy group, 4-biphenylyloxy group), anthryloxy group and thelike. Preferred are a phenoxy group and a biphenylyloxy group, and morepreferred is a phenoxy group.

The “aralkyloxy group” is an aralkyloxy group wherein the “aryl moiety”is the above-defined “aryl group” and the “alkyl moiety” is a linear orbranched chain alkyl group having 1 to 4 carbon atoms, which isexemplified by benzyloxy group, phenethyloxy group, 3-phenylpropyloxygroup and the like. Preferred is a benzyloxy group.

Preferably, it is a C₆₋₁₄ aryl C₁₋₄ alkyloxy group for R¹, R², R³ andR⁴.

The “lower cycloalkyl group” is a cycloalkyl group having 3 to 7 carbonatoms, which is exemplified by cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group and cycloheptyl group. Preferred isa cycloalkyl group having 5 to 7 carbon atoms, and particularlypreferred is a cyclohexyl group.

Preferably, it is a C₃₋₇ cycloalkyl group for Z.

The “lower cycloalkylalkyloxy group” is a cycloalkylalkyloxy groupwherein the “cycloalkyl moiety” is the above-defined “lower cycloalkylgroup” and the “alkyl moiety” is the above-defined “lower alkyl group”,which is exemplified by cyclopropylmethyloxy group, cyclobutylmethyloxygroup, cyclopentylmethyloxy group, cyclohexylmethyloxy group,cycloheptylmethyloxy group, 2-cyclopropylethyloxy group,2-cyclobutylethyloxy group, 2-cyclopentylethyloxy group,2-cyclohexylethyloxy group, 2-cycloheptylethyloxy group,3-cyclohexylpropyloxy, 4-cyclohexylbutyloxy group and the like.Preferred is a C₃₋₇ cycloalkyl C₁₋₄ alkyloxy group, more preferred is aC₅₋₇ cycloalkyl C₁₋₄ alkyloxy group, and particularly preferred is acyclohexyl C₁₋₄ alkyloxy group.

Preferably, it is a C₅₋₇ cycloalkyl C₁₋₄ alkyloxy group for R¹, R², R³and R⁴.

The “lower alkenyl group” is a linear or branched chain alkenyl grouphaving 2 to 6 carbon atoms, which is exemplified by vinyl group,1-propenyl group, allyl group, 1-methyl-2-propenyl group, 1-butenylgroup, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenylgroup, 1-hexenyl group, 2-hexenyl group and the like. Preferred is alinear or branched chain alkenyl group having 2 to 4 carbon atoms.

Preferably, it is a C₂₋₄ alkenyl group for R¹³.

The “lower alkylsulfonyl group” is an alkylsulfonyl group wherein the“alkyl moiety” is the above-defined “lower alkyl group”, which isexemplified by methylsulfonyl group, ethylsulfonyl group, propylsulfonylgroup, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonylgroup, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonylgroup, isopentylsulfonyl group, tert-pentylsulfonyl group, hexylsulfonylgroup and the like. Preferred is a C₁₋₄ alkylsulfonyl group.

Preferably, it is a C₁₋₄ alkylsulfonyl group for R¹³.

The “lower alkylcarbonyl group” is an alkylcarbonyl group wherein the“alkyl moiety” is the above-defined “lower alkyl group”, which isexemplified by acetyl group, propionyl group, butyryl group, isobutylgroup, valeryl group, isovaleryl group, pivaloyl group, pentanoyl group,hexanoyl group and the like. Preferred is a C₁₋₄ alkylcarbonyl groupwherein the “alkyl moiety” is a linear or branched chain alkyl grouphaving 1 to 4 carbon atoms.

Preferably, it is a C₁₋₄ alkylcarbonyl group for R¹³.

When R is a group represented by —COOR⁷ or —X¹-A¹-COOR⁷, and R⁷ is ahydrogen atom, this carboxy group may form a salt. As the salt, alkalimetal salts (e.g., potassium salt, sodium salt etc.), alkaline earthmetal salts (e.g., calcium salt, magnesium salt etc.) and the like canbe mentioned. Preferred is an alkali metal salt.

The tetrazole ring in the tetrazolyl group for R may form an alkalimetal salt. As such alkali metal salt, potassium salt, sodium salt andthe like can be mentioned.

The “lower cycloalkane” that may be formed by R⁹ and R¹⁰ together with acarbon atom bonded thereto is cycloalkane having 3 to 7 carbon atoms,which is exemplified by cyclopropane, cyclobutane, cyclopentane,cyclohexane and cycloheptane. Preferred is cycloalkane having 5 to 7carbon atoms, and particularly preferred is cyclopentane or cyclohexane.

The “5- to 7-membered hetero ring optionally further having at least onehetero atom selected from the group consisting of nitrogen atom, oxygenatom and sulfur atom” that may be formed by R⁹ and R¹⁰ together with acarbon atom bonded thereto is preferably a “saturated 5- to 7-memberedhetero ring optionally further having 1 to 3 hetero atoms selected fromthe group consisting of nitrogen atom, oxygen atom and sulfur atom”,which is exemplified by tetrahydropyran, thiane and the like,particularly preferably tetrahydropyran.

The “aromatic heterocyclic group” for B is a “monocyclic or fused 5- to14-membered aromatic heterocyclic group containing 1-3 hetero atomsselected from the group consisting of nitrogen atom, oxygen atom andsulfur atom”, which is exemplified by furyl group, thienyl group,pyrrolyl group, oxazolyl group, isooxazolyl group, thiazolyl group,isothiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group,isoindolyl group, benzofuranyl group, benzothienyl group,benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group,indolizinyl group, quinolyl group, isoquinolyl group, quinazolinylgroup, cinnolinyl group, quinoxalinyl group, phthalazinyl group,acrydinyl group, phenazinyl group, naphthyridinyl group and the like.Preferred is a “monocyclic or fused 5- to 10-membered aromaticheterocyclic group containing 1 to 3 hetero atoms selected from thegroup consisting of nitrogen atom, oxygen atom and sulfur atom”, andfuryl group, thienyl group, pyrrolyl group, oxazolyl group, isooxazolylgroup, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolylgroup, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinylgroup, indolyl group, isoindolyl group, benzofuranyl group, benzothienylgroup, benzoimidazolyl group, benzothiazolyl group, benzoxazolyl groupand the like can be mentioned. Particularly preferred are thiazolylgroup, pyridyl group, benzothiazolyl group, benzoimidazolyl group andbenzoxazolyl group.

The “lower cycloalkylalkyloxy group” for R¹, R², R³ and R⁴ is optionallysubstituted by 1 to 3 substituents selected from the following. As suchsubstituent, halogen atom, C₁₋₄ alkyl group, C₁₋₄ haloalkyl group, C₁₋₄alkoxy group, carboxy group, hydroxyl group, cyano group, nitro group,amino group, alkoxycarbonyl group (alkoxy moiety has 1 to 4 carbonatoms) and the like can be mentioned.

The “optionally substituted lower cycloalkylalkyloxy group” for R¹, R²,R³ and R⁴ is preferably 2-cyclohexylethyloxy group.

The “aralkyloxy group” for R¹, R², R³ and R⁴ is optionally substitutedby 1 to 3 substituents selected from the following. As such substituent,halogen atom, C₁₋₄ alkyl group, C₁₋₄ haloalkyl group, C₁₋₄ alkoxy group,carboxy group, hydroxyl group, cyano group, nitro group, amino group,alkoxycarbonyl (alkoxy moiety has 1 to 4 carbon atoms) group and thelike can be mentioned. Preferable substituent is carboxy group.

The “optionally substituted aralkyloxy group” for R¹, R², R³ and R⁴ ispreferably benzyloxy group, carboxybenzyloxy group and the like.

The “lower alkyl group” for R⁸ is optionally substituted by asubstituent selected from the group consisting of a lower alkoxy group,an aryloxy group, —N(R¹¹)(R¹²) (R¹¹ and R¹² are each independently ahydrogen atom or a lower alkyl group or may form, together with anitrogen atom bonded thereto, a 5- to 7-membered hetero ring optionallyfurther having at least one hetero atom selected from the groupconsisting of nitrogen atom, oxygen atom and sulfur atom), a carboxygroup, a lower cycloalkyl group and an optionally substituted arylgroup.

The “optionally substituted aryl group” which is a substituent on the“lower alkyl group” for R⁸ is optionally substituted by 1 to 3substituents selected from the following. As such substituent, halogenatom, C₁₋₄ alkyl group, C₁₋₄ haloalkyl group, C₁₋₄ alkoxy group, carboxygroup, hydroxyl group, cyano group, nitro group, amino group,alkoxycarbonyl group (alkoxy moiety has 1 to 4 carbon atoms) and thelike can be mentioned. Preferable substituents are halogen atom and C₁₋₄haloalkyl group.

The “5- to 7-membered hetero ring optionally further having at least onehetero atom selected from the group consisting of nitrogen atom, oxygenatom and sulfur atom” that may be formed by R¹¹ and R¹² together withthe nitrogen atom bonded thereto is preferably “a saturated orunsaturated 5- to 7-membered hetero ring optionally further having 1-3hetero atoms selected from the group consisting of nitrogen atom, oxygenatom and sulfur atom”, which is exemplified by a hetero ring selectedfrom the group consisting of

particularly preferably

The “lower alkyl group” for R¹³ is optionally substituted by asubstituent selected from the group consisting of C₃₋₇ cycloalkyl group,optionally substituted aryl group, optionally substituted heterocyclicgroup and hydroxyl group.

The “optionally substituted aryl group” which is a substituent on the“lower alkyl group” for R¹³ is optionally substituted by 1 to 3substituents selected from the following. As such substituent, halogenatom, C₁₋₄ alkyl group, C₁₋₄ haloalkyl group, C₁₋₄ alkoxy group, carboxygroup, hydroxyl group, cyano group, nitro group, amino group,alkoxycarbonyl group (alkoxy moiety has 1 to 4 carbon atoms) and thelike can be mentioned. Preferable substituent is a halogen atom or C₁₋₄haloalkyl group.

The “optionally substituted heterocyclic group” which is a substituenton the “lower alkyl group” for R¹³ is preferably a “saturated orunsaturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atomand sulfur atom”, which is exemplified by furyl group, thienyl group,pyrrolyl group, oxazolyl group, isooxazolyl group, thiazolyl group,isothiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, tetrahydrofurylgroup, tetrahydrothienyl group, pyrrolidinyl group, pyrazolidinyl group,imidazolidinyl group, oxazolidinyl group, thiazolidinyl group,tetrahydropyranyl group, dioxanyl group, piperidinyl group, piperazinylgroup, morpholinyl group and the like, with preference given totetrahydropyranyl group.

The “optionally substituted hetero ring” which is a substituent on the“lower alkyl group” for R¹³ is optionally substituted by 1 to 3substituents selected from the following. As such substituent, halogenatom, C₁₋₄ alkyl group, C₁₋₄ haloalkyl group, C₁₋₄ alkoxy group, carboxygroup, hydroxyl group, cyano group, nitro group, amino group,alkoxycarbonyl group (alkoxy moiety has 1 to 4 carbon atoms) and thelike can be mentioned.

The “lower alkylcarbonyl group” for R¹³ is optionally substituted by ahydroxyl group or a lower alkoxy group.

As the lower alkoxy group which is a substituent on the “loweralkylcarbonyl group” for R¹³, the above-defined “lower alkoxy group” canbe mentioned, with preference given to C₁₋₄ alkoxy group.

The “lower cycloalkane” that may be formed by R¹⁸ and R¹⁹ together witha carbon atom bonded thereto is cycloalkane having 3 to 7 carbon atoms,which is exemplified by cyclopropane, cyclobutane, cyclopentane,cyclohexane and cycloheptane. It is preferably cycloalkane having 5 to 7carbon atoms, and particularly preferably cyclopentane or cyclohexane.

The “5- to 7-membered hetero ring optionally further having at least onehetero atom selected from the group consisting of nitrogen atom, oxygenatom and sulfur atom” that may be formed by R¹⁸ and R¹⁹ together with acarbon atom bonded thereto is preferably, a “saturated 5- to 7-memberedhetero ring optionally further having 1 to 3 hetero atoms selected fromthe group consisting of nitrogen atom, oxygen atom and sulfur atom”,which is exemplified by tetrahydropyran, thiane and the like,particularly preferably tetrahydropyran.

The lower alkylene group for A² is optionally substituted by a lowercycloalkyl group. As such lower cycloalkyl group, cycloalkyl grouphaving 3 to 7 carbon atoms can be mentioned, which is exemplified bycyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl groupand cycloheptyl group. It is preferably a cycloalkyl group having 5 to 7carbon atoms, particularly preferably a cyclohexyl group.

The “lower alkylene group optionally substituted by a lower cycloalkylgroup” for A² is preferably a “C₁₋₄ alkylene group optionallysubstituted by C₃₋₇ cycloalkyl group”, more preferably,

The “lower cycloalkyl group” for Z is preferably a C₃₋₇ cycloalkylgroup, more preferably a cyclopentyl group or a cyclohexyl group, stillmore preferably a cyclohexyl group.

The “lower cycloalkyl group” for Z may be substituted by (a) a halogenatom, (b) a C₁₋₆ alkyl group, (c) a C₁₋₄ haloalkyl group, (d) a carboxygroup, (e) a C₃₋₇ cycloalkyl group, (f) a C₁₋₄ alkoxy group, (g) aheterocyclic group optionally substituted by a C₁₋₄ alkyl group or (h) aphenyl group, wherein said phenyl group is further optionallysubstituted by 1 to 5 (preferably 1 to 3) halogen atoms. Suchsubstituent of the “lower cycloalkyl group” is preferably a phenyl groupoptionally substituted by 1 to 3 halogen atoms, more preferably a phenylgroup.

The “aryl group” for Z is preferably a phenyl group or a biphenylylgroup (e.g., 2-biphenylyl group, 3-biphenylyl group, 4-biphenylylgroup), more preferably a phenyl group.

The “aryl group” for Z is optionally substituted by 1 to 5 (preferably 1to 3) substituents selected from the following;

-   (a) a heterocyclic group optionally substituted by a substituent    selected from the group consisting of a lower alkyl group and a    lower alkylcarbonyl group,-   (b) a lower cycloalkyl group optionally substituted by a substituent    selected from the group consisting of a hydroxyl group, an oxo    group, a halogen atom and a lower alkyl group,-   (c) a carboxy group,-   (d) a halogen atom,-   (e) an alkyl group,-   (f) a lower haloalkyl group,-   (g) a lower alkylamino group,-   (h) a di(lower alkyl)amino group,-   (i) a lower alkylthio group and-   (j) a lower alkoxy group.

The “heterocyclic group” of the “heterocyclic group optionallysubstituted by a substituent selected from the group consisting of loweralkyl group and lower alkylcarbonyl group” is preferably a “saturated orunsaturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atomand sulfur atom”, which is exemplified by furyl group, thienyl group,pyrrolyl group, oxazolyl group, isooxazolyl group, thiazolyl group,isothiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, tetrahydrofurylgroup, tetrahydrothienyl group, pyrrolidinyl group, pyrazolidinyl group,imidazolidinyl group, oxazolidinyl group, thiazolidinyl group,tetrahydropyranyl group, dioxanyl group, piperidinyl group, piperazinylgroup, morpholinyl group and the like. It is preferably piperidinylgroup, morpholinyl group, piperazinyl group, pyrrolidinyl group,pyrrolyl group or tetrahydropyranyl group, more preferably a groupselected from the group consisting of

particularly preferably a group selected from the group consisting of

The substituent on said “heterocyclic group” is preferably a C₁₋₄ alkylgroup or a C₁₋₄ alkylcarbonyl group (alkyl moiety has 1 to 4 carbonatoms).

The “lower cycloalkyl” of the “lower cycloalkyl group optionallysubstituted by a substituent selected from the group consisting ofhydroxyl group, an oxo group, a halogen atom and lower alkyl group” ispreferably C₃₋₇ cycloalkyl group, more preferably cyclohexyl group. The“lower cycloalkyl group” is optionally substituted by 1 to 5 (preferably1 to 3) substituents selected from the group consisting of a hydroxylgroup, an oxo group, a halogen atom and a lower alkyl group. Thesubstituent on the “lower cycloalkyl group” is preferably a hydroxylgroup, an oxo group, a halogen atom or a C₁₋₄ alkyl group.

As the “halogen atom” which is a substituent on “aryl group” for Z, theabove-defined “halogen atom” can be preferably mentioned, such asfluorine atom, chlorine atom and bromine atom.

The “alkyl group” which is a substituent on the “aryl group” for Z ispreferably a linear or branched chain alkyl group having 1 to 8 carbonatoms, which is exemplified by methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, isopentyl group, neopentyl group,tert-pentyl group, 1-ethylpropyl group, hexyl group, heptyl group,1-propylbutyl group, octyl group and the like.

The “lower haloalkyl group” which is a substituent on the “aryl group”for Z is the above-defined “lower haloalkyl group”, which is preferablya C₁₋₄ haloalkyl group.

The “lower alkylamino group” which is a substituent on the “aryl group”for Z is an alkylamino group wherein the “alkyl moiety” is theabove-defined “lower alkyl group”, which is exemplified by methylaminogroup, ethylamino group, propylamino group, isopropylamino group,butylamino group, isobutylamino group, sec-butylamino group,tert-butylamino group, pentylamino group, isopentylamino group,neopentylamino group, tert-pentylamino group, hexylamino group and thelike. It is preferably a C₁₋₄ alkylamino group.

The “di(lower alkyl)amino group” which is a substituent on the “arylgroup” for Z is dialkylamino group wherein the “alkyl moiety” is theabove-defined “lower alkyl group”, which is exemplified by dimethylaminogroup, diethylamino group, dipropylamino group, diisopropylamino group,dibutylamino group, diisobutylamino group, di(sec-butyl)amino group,di(tert-butyl)amino group, dipentylamino group, diisopentylamino group,di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylaminogroup, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and thelike. Preferred is a di(C₁₋₄ alkyl)amino group.

The “lower alkylthio group” which is a substituent on the “aryl group”for Z is alkylthio group wherein the “alkyl moiety” is the above-defined“lower alkyl group”, which is exemplified by methylthio group, ethylthiogroup, propylthio group, isopropylthio group, butylthio group,isobutylthio group, sec-butylthio group, tert-butylthio group,pentylthio group, isopentylthio group, neopentylthio group,tert-pentylthio group, hexylthio group and the like. It is preferably aC₁₋₄ alkylthio group.

The “lower alkoxy group” which is a substituent on the “aryl group” forZ is the above-defined “lower alkoxy group”, preferably a C₁₋₄ alkoxygroup.

The “aromatic heterocyclic group” for Z is preferably a “monocycle orfused 5- to 10-membered aromatic heterocyclic group containing 1-3hetero atoms selected from the group consisting of nitrogen atom, oxygenatom and sulfur atom”, and furyl group, thienyl group, pyrrolyl group,oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group,imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, indolyl group, isoindolyl group,benzofuranyl group, benzothienyl group, benzoimidazolyl group,benzothiazolyl group, benzoxazolyl group and the like can be mentioned.It is particularly preferably a thiazolyl group or a pyridyl group.

The “aromatic heterocyclic group” for Z is optionally substituted by 1to 5 (preferably 1 to 3) substituents selected from the following;

-   (a) a heterocyclic group optionally substituted by C₁₋₄ alkyl group,-   (b) a C₁₋₆ alkyl group,-   (c) an aryl group optionally substituted by a halogen atom or a C₁₋₄    haloalkyl group,-   (d) a halogen atom,-   (e) a C₁₋₄ haloalkyl group,-   (f) a carboxy group,-   (g) a C₃₋₇ cycloalkyl group and-   (h) a C₁₋₄ alkoxy group.

Such substituent is preferably (a) a heterocyclic group, (b) a C₁₋₆alkyl group or (c) an aryl group optionally substituted by a halogenatom or a C₁₋₄ haloalkyl group.

The “heterocyclic group” which is a substituent on the “aromaticheterocyclic group” for Z is preferably a “saturated or unsaturated 5-to 7-membered heterocyclic group containing 1 to 3 hetero atoms selectedfrom the group consisting of nitrogen atom, oxygen atom and sulfuratom”, which is exemplified by furyl group, thienyl group, pyrrolylgroup, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolylgroup, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, tetrahydrofuryl group,tetrahydrothienyl group, pyrrolidinyl group, pyrazolidinyl group,imidazolidinyl group, oxazolidinyl group, thiazolidinyl group,tetrahydropyranyl group, dioxanyl group, piperidinyl group, piperazinylgroup, morpholinyl group and the like. It is preferably piperidinylgroup, morpholinyl group, piperazinyl group, tetrahydropyranyl group,pyrrolidinyl group or pyrrolyl group, more preferably a group selectedfrom the group consisting of

particularly preferably

The “aryl group optionally substituted by a halogen atom or a C₁₋₄haloalkyl group” which is a substituent on the “aromatic heterocyclicgroup” for Z is preferably a “phenyl group optionally substituted by ahalogen atom or a C₁₋₄ haloalkyl group”.

The “piperazinyl group” for Z is optionally substituted by 1 to 5(preferably 1 to 3) substituents selected from the following;

-   (a) a phenyl group,-   (b) a phenyl lower alkyl group,-   (c) a benzoyl group optionally substituted by a halogen atom and-   (d) a phenyl lower alkoxycarbonyl group.

The “phenyl lower alkyl group” which is a substituent on the“piperazinyl group” for Z is a phenylalkyl group wherein the “alkylmoiety” is the above-defined “lower alkyl group”, which is exemplifiedby benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropylgroup and the like. Preferably, it is a phenyl C₁₋₄ alkyl group.

The “benzoyl group optionally substituted by a halogen atom” which is asubstituent on the “piperazinyl group” for Z is preferably a benzoylgroup optionally substituted by 1 to 5 the above-defined “halogenatoms”, which is exemplified by chlorobenzoyl group, bromobenzoyl groupand the like.

The “phenyl lower alkoxycarbonyl group” which is a substituent on the“piperazinyl group” for Z is a phenylalkoxycarbonyl group wherein the“alkoxy moiety” is the above-defined “lower alkoxy group”, which isexemplified by a benzyloxycarbonyl group and the like. Preferably, it isa phenyl C₁₋₄ alkoxycarbonyl group.

In the formula [I], preferable substituents are as follows.

W is preferably a sulfur atom.

R is preferably —COOR⁷ wherein R⁷ is a hydrogen atom.

R¹, R², R³ and R⁴ are preferably hydrogen atoms.

A is preferably —(CH₂)_(m)—X—

wherein

-   X is a group represented by —N(R⁸)— wherein R⁸ is a hydrogen atom or    a C₁₋₆ alkyl group, wherein said C₁₋₆ alkyl group is optionally    substituted by a substituent selected from the group consisting of a    C₁₋₄ alkoxy group, an aryloxy group, —N(R¹¹)(R¹²) (R¹¹ and R¹² are    each independently a hydrogen atom or a C₁₋₄ alkyl group or may    form, together with a nitrogen atom bonded thereto, a 5- to    7-membered hetero ring optionally further having at least one hetero    atom selected from the group consisting of nitrogen atom, oxygen    atom and sulfur atom), a carboxy group, a C₃₋₇ cycloalkyl group and    an optionally substituted aryl group, and-   m is 0 or an integer of 1 to 3.

B is preferably a phenyl group, a thiazolyl group, a pyridyl group, abenzothiazolyl group, a benzoimidazolyl group or a benzoxazolyl group,more preferably a phenyl group.

R⁵ is preferably a hydrogen atom.

Z is preferably

-   (1) a C₃₋₇ cycloalkyl group    (wherein said C₃₋₇ cycloalkyl group is optionally substituted by a    phenyl group optionally substituted by a halogen atom),-   (2) an aryl group    (wherein said aryl group is optionally substituted by a substituent    selected from the group consisting of    -   (a) a heterocyclic group optionally substituted by a C₁₋₄ alkyl        group or a C₁₋₄ alkylcarbonyl group,    -   (b) a C₃₋₇ cycloalkyl group optionally substituted by a        substituent selected from the group consisting of a hydroxyl        group, an oxo group, a halogen atom and a C₁₋₄ alkyl group,    -   (c) a carboxy group,    -   (d) a halogen atom,    -   (e) a C₁₋₈ alkyl group,    -   (f) a C₁₋₄ haloalkyl group,    -   (g) a C₁₋₄ alkylamino group,    -   (h) a di(C₁₋₄ alkyl)amino group,    -   (i) a C₁₋₄ alkylthio group and    -   (j) a C₁₋₄ alkoxy group) or-   (3) an aromatic heterocyclic group    (wherein said aromatic heterocyclic group is optionally substituted    by a substituent selected from the group consisting of    -   (a) a heterocyclic group,    -   (b) a C₁₋₄ alkyl group and    -   (c) a phenyl group optionally substituted by a halogen atom or a        C₁₋₄ haloalkyl group).

Z is more preferably an aryl group optionally substituted by asubstituent selected from the group consisting of

-   (a) a heterocyclic group optionally substituted by a C₁₋₄ alkyl    group or a C₁₋₄ alkylcarbonyl group,-   (b) a C₃₋₇ cycloalkyl group optionally substituted by a substituent    selected from the group consisting of a hydroxyl group, an oxo    group, a halogen atom and a C₁₋₄ alkyl group,-   (c) a carboxy group,-   (d) a halogen atom,-   (e) a C₁₋₈ alkyl group,-   (f) a C₁₋₄ haloalkyl group,-   (g) a C₁₋₄ alkylamino group,-   (h) a di(C₁₋₄ alkyl)amino group and-   (i) a C₁₋₄ alkylthio group.

Z is further preferably a phenyl group substituted by a substituentselected from the group consisting of

-   (a) a cyclohexyl group or a cyclopentyl group optionally substituted    by a substituent selected from the group consisting of a hydroxyl    group, an oxo group, a halogen atom and a C₁₋₄ alkyl group,-   (b) a heterocyclic group optionally substituted by a C₁₋₄ alkyl    group or a C₁₋₄ alkylcarbonyl group (wherein said heterocyclic group    is selected from the group consisting of a piperidinyl group, a    morpholinyl group, a piperazinyl group, a tetrahydropyranyl group, a    pyrrolidinyl group and a pyrrolyl group) and-   (c) C₁₋₈ alkyl groups.

Z is particularly preferably a phenyl group substituted by a cyclohexylgroup optionally substituted by a substituent selected from the groupconsisting of a hydroxyl group, an oxo group, a halogen atom and a C₁₋₄alkyl group.

For R⁶, Y is preferably —O—, —N(R¹³)— or —N(R¹⁴)—CO—

wherein

-   R¹³ is a hydrogen atom, a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group,    wherein said C₁₋₄ alkyl group is optionally substituted by a    substituent selected from the group consisting of a C₃₋₇ cycloalkyl    group, an optionally substituted aryl group and an optionally    substituted heterocyclic group,-   R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group, and s1 is 0 or 1.

A² is preferably a methylene group.

The “pharmaceutically acceptable salt” may be any salt as long as itforms a non-toxic salt with the compound represented by theabove-mentioned formula [I], and can be obtained by reacting withinorganic acids such as hydrochloric acid, sulfuric acid, phosphoricacid, hydrobromic acid and the like; organic acids such as oxalic acid,malonic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acidand the like; inorganic bases such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxideand the like; organic bases such as methylamine, diethylamine,triethylamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine,N-methyl-D-glucamine and the like; or amino acids such as lysin,histidine, arginine, alanine and the like. The present invention alsoencompasses water-containing product, hydrate and solvate of eachcompound.

The compound represented by the above-mentioned formula [I] containsvarious isomers. For example, E-form and Z-form are present as geometricisomers, and when an asymmetric carbon atom is present, enantiomer anddiastereomer are present as stereoisomers based thereon. In some cases,a tautomer may be present. Accordingly, the present inventionencompasses all of these isomers and mixtures thereof.

The present invention encompasses prodrug and metabolite of the compoundof the formula [I].

A “prodrug” is a derivative of the compound of the present invention,which has a chemically or metabolically decomposable group, and, afteradministration to a living organism, restores to the original compoundto show the inherent efficacy. It includes a complex free of covalentbond and salt.

For example, known ester derivatives can be used as prodrugs in thefield of pharmaceutical drugs. To be specific, ester derivatives whereinR is a group represented by the following formula can be mentioned.

When the compound of the present invention is used as a pharmaceuticalpreparation, it is generally admixed with pharmaceutically acceptablecarrier, excipient, diluent, extender, disintegrant, stabilizer,preservative, buffer, emulsifier, aromatic, coloring agent, sweeteningagent, thickening agent, corrigent, dissolution aids and otheradditives, which are known per se and specifically exemplified by water,vegetable oil, alcohols such as ethanol, benzyl alcohol etc.,polyethylene glycol, glycerol triacetate, gelatin, lactose, carbohydratesuch as starch etc., magnesium stearate, talc, lanolin, vaseline and thelike, and prepared into the form of tablet, pill, powder, granule,suppository, injection, eye drop, liquid, capsule, troche, aerosol,elixir, suspension, emulsion, syrup and the like by a conventionalmethod, which can be administered systemically or topically, and orallyor parenterally.

The dose of the compound of the present invention varies depending onthe age, body weight, symptom, disease to be treated, administrationmethod and the like, but it is generally administered in the range of 50mg to 800 mg per dose for an adult once to several times a day.

The compound [I] of the present invention can be administered to mammals(human, mouse, rat, rabbit, dog, cat, bovine, pig, monkey etc.) as aPTP1B inhibitor, a drug for the prophylaxis or treatment of diabetes, adrug for the prophylaxis or treatment of diabetic complications(retinopathy, nephropathy, neuropathy, cardiac infarction and cerebralinfarction based on arteriosclerosis, etc.), a drug for the prophylaxisor treatment of hyperlipidemia, a drug for the prophylaxis or treatmentof obesity, neurodegenerative disease and the like or a drug for theprophylaxis or treatment of a disease mediated by PTP1B.

The compound [I] of the present invention can be administered to amammal together with other therapeutic agents for diabetes for thepurpose of prophylaxis or treatment of diabetes or diabeticcomplications. In the present invention, “therapeutic agents fordiabetes” include therapeutic agents for diabetic complications. Inaddition, the compound [I] of the present invention can be administeredto a mammal together with other therapeutic agents for hyperlipidemiafor the purpose of prophylaxis or treatment of hyperlipidemia.

In the case of combined administration, the compound of the presentinvention can be administered simultaneously with a differenttherapeutic agent for diabetes or a different therapeutic drug forhyperlipidemia (hereinafter combination drug) or administered at certaintime intervals. In the case of combined administration, a pharmaceuticalcomposition containing the compound of the present invention and acombination drug can be administered. Alternatively, a pharmaceuticalcomposition containing the compound of the present invention and apharmaceutical composition containing a combination drug may beadministered separately. The administration route of each pharmaceuticalcomposition may be the same or different.

In the case of a combined administration, the compound of the presentinvention can be administered once to several times a day in the rangeof 50 mg to 800 mg per dose, or may be administered at a lower dose. Acombination drug can be administered at a dose generally employed forthe prophylaxis or treatment of diabetes or for the prophylaxis ortreatment of hyperlipidemia, or may be administered at a lower dose.

As other therapeutic agents for diabetes to be used for the combinedadministration, insulin secretagogue, sulfonylurea, sulfonamide,biguanide, α glucosidase inhibitor, insulin preparation, insulinsensitizer and the like can be mentioned. For example, nateglide,glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide,glyclopyramide, tolazamide, glybuzole, metformin hydrochloride, buforminhydrochloride, voglibose, acarbose, insulin, pioglitazone hydrochlorideand the like can be used for combined administration with the compoundof the present invention.

As other therapeutic drugs for hyperlipidemia to be used for thecombined administration, statin drugs can be mentioned. For example,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,cerivastatin and the like can be used for combined administration withthe compound of the present invention.

Now, one example of the production methods of the compounds used topractice the present invention is shown below. However, the productionmethod of the compound of the present invention is not limited to theexample.

Even in the absence of description in the production methods, aprotecting group may be introduced into functional groups as necessaryand deprotected at a suitable stage, the order of each production methodand step is exchanged and the like to efficiently perform production.

The treatment after reaction in each step may be performed according toa method generally employed, and conventional methods such as isolationand purification, crystallization, recrystallization, silica gelchromatography, preparative HPLC and the like are appropriatelyselected, or used in combination.

Production Method 1

In this Production Method, compound [I] wherein W is a sulfur atom isproduced.

wherein R_(A) is —COOR^(7′) or —X¹-A¹-COOR^(7′) (R^(7′) is a lower alkylgroup), Hal is a halogen atom such as a bromine atom, a chlorine atomand the like, and other symbols are as defined above.Step 1

The compound [2] can be obtained by reacting compound [1] with athiocarbonylation agent such as a Lawesson's reagent, phosphoruspentasulfide and the like in a solvent. As the solvent, tetrahydrofuran(THF), 1,2-dimethoxyethane (DME), toluene, xylene, chloroform,dichloromethane, dioxane and the like, or a mixed solvent thereof can bementioned. The reaction temperature is preferably 50° C.-100° C.

Step 2

The compound [I]-1 can be obtained by reacting compound [2] withcompound [3] in the presence or absence of a base in a solvent underheating. As the solvent, acetonitrile, alcohols (methanol, ethanol,isopropyl alcohol etc.), THF, DME, dioxane and the like, or a mixedsolvent thereof can be mentioned. As the base, sodium hydrogencarbonate, potassium hydrogen carbonate and the like can be mentioned.

Production Method 2

In this Production Method, compound [I] wherein W is an oxygen atom isproduced.

wherein each symbol is as defined above.Step 3

The compound [I]-2 can be obtained by reacting compound [1] withcompound [3] in a solvent under heating. As the solvent, acetonitrile,alcohols (methanol, ethanol, isopropyl alcohol etc.), xylene, tolueneand the like, or a mixed solvent thereof can be mentioned.

Production Method 3

In this Production Method, compound [I] wherein W is a sulfur atom and Ais —(CH₂)_(m)—N(R⁸)— is produced.

wherein R^(8′) is —SO₂R¹⁶ or a lower alkyl group, wherein said loweralkyl group is optionally substituted by a substituent selected from thegroup consisting of a lower alkoxy group, an aryloxy group,—N(R¹¹)(R¹²), a carboxy group, a lower cycloalkyl group and anoptionally substituted aryl group, L is a leaving group such as aniodine atom, a bromine atom, a chlorine atom and the like, and othersymbols are as defined above.Step 4

The compound [6] can be obtained by reacting compound [4] with1,1′-thiocarbonyldiimidazole, thiophosgene and the like in a solvent inthe presence or absence of a base, then reacting with ammonia. As thesolvent, chloroform, dichloromethane, dichloroethane, THF, DME, dioxane,toluene and the like, or a mixed solvent thereof can be mentioned. Asthe base, triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), sodium hydride and the likecan be mentioned. The reaction temperature is preferably −20° C.-50° C.

Step 5

The compound [I]-3 can be obtained by reacting compound [6] withcompound [3] in a solvent under heating in the presence or absence of abase. As the solvent, acetonitrile, alcohols (methanol, ethanol,isopropyl alcohol etc.), THF, DME, dioxane and the like, or a mixedsolvent thereof can be mentioned. As the base, sodium hydrogencarbonate, potassium hydrogen carbonate and the like can be mentioned.

Step 6

The compound [I]-4 can be obtained by reacting compound [I]-3 withcompound [7] in a solvent in the presence of a base. As the solvent,dimethylformamide, dimethylacetamide, THF, DME, dioxane,hexamethylphosphoramide (HMPA), dimethyl sulfoxide (DMSO) and the like,or a mixed solvent thereof can be mentioned. As the base, sodiumhydride, potassium carbonate, sodium carbonate and the like can bementioned. The reaction temperature is preferably 0° C.-100° C.

Production Method 4

In this Production Method, compound [I] wherein R⁷ is a hydrogen atomwhen R is —COOR⁷ or —X¹-A¹-COOR⁷, or a salt thereof is produced.Production Method 4

wherein R_(B) is —COOH or —X¹-A¹-COOH, R_(C) is —COOM or —X¹-A¹-COOM (Mis an alkali metal), and other symbols are as defined above.Step 7

The compound [I]-6 can be obtained by hydrolyzing compound [I]-5.Hydrolysis can be performed according to conventional methods. Forexample, a method comprises hydrolyzing in a solvent in the presence ofan acid (including a Lewis acid) or a base can be mentioned. As thesolvent, alcohols (methanol, ethanol, isopropyl alcohol etc.),tetrahydrofuran, dioxane, DME, N,N-dimethylformamide (DMF), DMSO, waterand the like, or a mixed solvent thereof can be mentioned. As the acid,hydrochloric acid, trifluoroacetic acid, sulfuric acid and the like canbe mentioned. As the base, alkali metal hydroxide (sodium hydroxide,potassium hydroxide etc.), potassium carbonate, sodium carbonate and thelike can be mentioned. The reaction temperature is not particularlylimited, and the reaction can be carried out under cooling to underheating.

Step 8

The compound [I]-7 can be obtained by reacting compound [I]-6 withalkali metal hydroxide [8], according to conventional methods. Alkalimetal hydroxide includes sodium hydroxide, potassium hydroxide and thelike. This Step can be conducted in a solvent. As the solvent, alcohols(methanol, ethanol etc.), tetrahydrofuran, dioxane, DME and the like, ora mixed solvent thereof can be mentioned. The reaction temperature isnot particularly limited, and the reaction can be carried out undercooling to under heating.

Production Method 5

In this Production Method, compound [I] wherein R is a tetrazolyl groupis produced.Production Method 5

wherein each symbol is as defined above.Step 9

The compound [I]-8 can be obtained by reacting compound [9] produced inthe same manner as in the aforementioned Production Method 1-3 withtrimethylsilylazide and dibutyltin oxide in a solvent. As the solvent,toluene, xylene, benzene and the like, or a mixed solvent thereof can bementioned. The reaction temperature is preferably 50° C.-150° C.

Production Method 6

In this Production Method, compound [I] wherein R⁶ is —N(R¹³)—CH₂-Z isproduced.

wherein each symbol is as defined above.Step 10

The compound [11] can be obtained by reducing compound [10]. Reductioncan be performed according to conventional methods. For example,compound [10] is subjected to catalytic reduction in a solvent in thepresence of a catalyst under a hydrogen atmosphere. As the solvent,alcohols (methanol, ethanol, isopropyl alcohol etc.), tetrahydrofuran,acetic acid and the like can be mentioned. As the catalyst, palladiumcatalysts such as palladium-carbon etc. and the like can be mentioned.

Step 11

The compound [I]-9 can be obtained by reacting compound [11] withcompound [12] in the presence of a reducing agent. As the reducingagent, sodium triacetoxyborohydride, sodium cyanoborohydride (NaBH₃CN)and the like can be mentioned. The reaction temperature is preferably 0°C.-40° C.

Step 12

The compound [I]-10 can be obtained by reacting compound [I]-9 withcompound [13] in a solvent in the presence of a base. This reaction canbe carried out in the same manner as in Step 6 of Production Method 3.

The Production Methods described in the present specification areexamples of the production methods of the compounds of the presentinvention, and compounds other than those explained in the above can bealso produced by combining conventional methods known in the field oforganic synthetic chemistry.

EXAMPLES

The compound represented by the formula [I] and Production Methods ofthe present invention are explained in detail by referring to ProductionExamples and Examples, which are not to be construed as limitative.

Production Example 1 4-cyclohexylbenzaldehyde (1) 4-cyclohexylbenzylAlcohol

Under a nitrogen stream, tetrahydrofuran (1.2 L, 15.0 v/w) was added to4-cyclohexylbenzoic acid (80.0 g, 0.382 mol) and then isobutylchlorocarbonate (52.0 ml, 0.401 mol) was added. Triethylamine (56.0 ml,0.401 mol) was added to the reaction mixture with stirring underice-cooling and the mixture was stirred at the same temperature for 30min. The resulting precipitate was collected by filtration. To asuspension of sodium borohydride (58.0 g, 1.53 mol) in tetrahydrofuran(160 ml, 2.0 v/w) prepared in a different reaction vessel was carefullyadded the above-mentioned filtrate with stirring under ice-cooling undera nitrogen stream. After stirring at room temperature for 1.5 hr,distilled water (160 ml, 2.0 v/w) was added with stirring underice-cooling. After stirring under ice-cooling for 20 min,2N-hydrochloric acid (825 ml, 4.3 eq) was added. After stirring at roomtemperature for 30 min, the mixture was extracted with ethyl acetate(400 ml) and the organic layer was washed successively with distilledwater (100 ml), 2N-aqueous sodium hydroxide solution (100 ml), distilledwater (100 ml) and saturated brine (100 ml), and dried over magnesiumsulfate (70 g). After filtration and solvent evaporation, the residuewas dried in vacuo to give the title compound (63.8 g, yield 87.8%) as awhite solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 1.23-1.41(5H,m), 1.67-1.78(5H,m), 2.47(1H,m),4.43(2H,s), 5.04(1H,brs), 7.15(2H,d,J=8.0 Hz), 7.21(2H,d,J=8.0 Hz).

(2) 4-cyclohexylbenzaldehyde

To a solution of 4-cyclohexylbenzyl alcohol (121.5 g, 0.639 mol)obtained in Production Example 1(1) in dimethyl sulfoxide (500 ml) wasadded triethylamine (249 ml, 1.79 mol). Pyridine-sulfur trioxide complex(163 g, 1.02 mol) was gradually added with stirring under ice-cooling,and the mixture was stirred at room temperature for 2 hr. Water (500 ml)was added dropwise to the reaction mixture with stirring underice-cooling, and the mixture was extracted with a mixed solvent (1:1) ofn-hexane and ethyl acetate, washed with saturated brine and dried oversodium sulfate. After filtration and solvent evaporation, the residuewas dried in vacuo to give the title compound (112 g, yield 93.4%) as acolorless oil.

¹H-NMR(300 MHz,CDCl₃) δ 1.20-1.53(5H,m), 1.72-1.95(5H,m),2.53-2.65(1H,m), 5.04(1H,brs), 7.37(2H,d,J=8.2 Hz), 7.81(2H,d,J=8.2 Hz),9.97(1H,s).

EXAMPLE 14-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoicacid (1) 1-(4-methoxycarbonylbenzyl)-2-thiourea

Under an argon atmosphere, to a suspension of methyl4-aminomethylbenzoate hydrochloride (170.0 g, 0.843 mol) in chloroform(850 ml, 5.0 v/w) were successively added 1,1′-thiocarbonyldiimidazole(purity 90%, 166.0 g, 0.843 mol) and triethylamine (123 ml, 0.885 mol).After stirring at room temperature for 3 hr, 28% aqueous ammonia (570ml, 8.43 mol) and methanol (170 ml, 1.0 v/w) were added and the mixturewas stirred overnight. n-Hexane (1700 ml, 10.0 v/w) and water (850 ml,5.0 v/w) were successively added to the reaction mixture and the mixturewas stirred at room temperature for 3 hrs. The precipitated crystalswere collected by filtration, washed successively with n-hexane (500 ml)and water (500 ml) and dried in vacuo to give the title compound (172.5g, yield 91.3%) as a colorless solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 3.84(3H,s), 4.40(1H,brs), 4.72(2H,brs),7.17(1H,brs), 7.41(2H,d,J=8.1 Hz), 7.93(2H,d,J=8.4 Hz), 8.07(1H,brs).

(2) methyl 4-((4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate

To a suspension of 1-(4-methoxycarbonylbenzyl)-2-thiourea (138.0 g,0.554 mol) obtained in Example 1(1) in acetonitrile (1380 ml, 10.0 v/w)were successively added 2-bromo-4′-nitroacetophenone (124.1 g, 0.554mol) and sodium bicarbonate (46.9 g, 0.559 mol), and the mixture washeated under reflux for 2 hr. After cooling to room temperature, water(1380 ml, 10.0 v/w) and n-hexane (690 ml, 5.0 v/w) were successivelyadded and the mixture was stirred for 1 hr. The precipitated crystalswere collected by filtration, washed successively with water (1000 ml)and n-hexane (500 ml) and dried in vacuo to give the title compound(183.9 g, yield 89.9%) as a yellow solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 3.83(3H,s), 4.63(2H,d,J=5.9 Hz), 7.49(1H,s),7.54(2H,d,J=8.1 Hz), 7.95(2H,d,J=8.1 Hz), 8.06(2H,d,J=9.3 Hz),8.23(2H,d,J=6.0 Hz), 8.43(1H,t,J=5.9 Hz).

(3) methyl4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate

Under an argon atmosphere, to a suspension of sodium hydride (content60%, 26.4 g, 0.661 mol) in N,N-dimethylformamide (530 ml, 2.5 v/w) weresuccessively added dropwise a solution of methyl4-((4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate (212.4 g, 0.575mol) obtained in Example 1(2) in N,N-dimethylformamide (743 ml, 3.5 v/w)and methyl iodide (41.2 ml, 0.661 mol) at 10° C. or below, and themixture was stirred at room temperature for 2 hr. Sodium hydride(content 60%, 2.3 g, 0.057 mol) was added and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was added dropwise towater (2120 ml, 10.0 v/w) at 10° C. or below, and, after stirring atroom temperature for 30 min., diisopropyl ether (848 ml, 4.0 v/w) wasadded and the mixture was stirred for 2 hr. The precipitated crystalswere collected by filtration, washed successively with diisopropyl ether(424 ml) and water (424 ml) and dried in vacuo to give the titlecompound (201.9 g, yield 91.4%) as a yellow solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 3.14(3H,s), 3.84(3H,s), 4.87(2H,s),7.48(2H,d,J=8.3 Hz), 7.61(1H,s), 7.96(2H,d,J=8.3 Hz), 8.11(2H,d,J=9.0Hz), 8.25(2H,d,J=9.0 Hz).

(4) methyl4-(N-(4-(4-aminophenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate

To a suspension of methyl4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate (200.0g, 0.522 mol) obtained in Example 1(3) in a mixture of ethanol (800 ml,4.0 v/w) and tetrahydrofuran (800 ml, 4.0 v/w) was added 10% palladiumcarbon (20.0 g) and the mixture was stirred overnight under a hydrogenatmosphere at 3 atm. The reaction mixture was filtered through celiteand 10% palladium carbon (20.0 g) was added to the filtrate. The mixturewas stirred under a hydrogen atmosphere at 3 atm for 3 hr. After celitefiltration and solvent evaporation, toluene (800 ml) was added to theresidue and the solvent was evaporated to give the title compound (182.5g, yield 99.0%) as a yellow solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 3.07(3H,s), 3.84(3H,s), 4.82(2H,s),5.18(2H,br), 6.54(2H,d,J=8.6 Hz), 6.78(1H,s), 7.45(2H,d,J=8.3 Hz),7.52(2H,d,J=8.5 Hz), 7.95(2H,d,J=8.2 Hz).

(5) methyl4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate

Under an argon stream, tetrahydrofuran (1000 ml, 5.7 v/w) was added tomethyl 4-(N-(4-(4-aminophenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate(174.0 g, 0.493 mol) obtained in Example 1(4) and dissolved therein. Asolution of 4-cyclohexylbenzaldehyde (120.6 g, 0.641 mol) obtained inProduction Example 1(2) in tetrahydrofuran (740 ml, 4.3 v/w) was added.Acetic acid (56.4 ml, 0.986 mol) was added and the mixture was stirredat room temperature for 1 hr. With stirring under ice-cooling, sodiumtriacetoxyborohydride (104.5 g, 0.493 mol) was added and the mixture wasstirred at room temperature for 1.5 hr. After ice-cooling, acetic acid(28.2 ml, 0.493 mol) and sodium triacetoxyborohydride (52.2 g, 0.246mol) were added and the mixture was stirred at room temperature for 1.5hr. The reaction mixture was ice-cooled and carefully added to asaturated aqueous sodium hydrogen carbonate solution (2262 ml, 13.0v/w). After stirring at room temperature for 1 hr, the mixture wasextracted with ethyl acetate (522 ml), and the organic layer was washedsuccessively with distilled water (174 ml) and saturated brine (522 ml)and dried over magnesium sulfate (50.0 g). The solvent was evaporatedand the obtained orange solid was purified by silica gel columnchromatography (developing solvent chloroform:ethyl acetate=99.5:0.5) togive the title compound (80.3 g, yield 31.0%) as a pale-yellow solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 1.16-1.47(5H,m), 1.65-1.80(5H,m),2.40-2.55(1H,m), 3.60(3H,s), 3.83(3H,s), 4.22(2H,d,J=5.5 Hz),4.81(2H,s), 6.32(1H,t,J=5.5 Hz), 6.57(1H,d,J=8.7 Hz), 6.77(1H,s),7.15(2H,d,J=8.1 Hz), 7.26(2H,d,J=8.1 Hz), 7.45(2H,d,J=8.3 Hz),7.53(2H,d,J=8.6 Hz), 7.94(2H,d,J=8.3 Hz).

(6) methyl4-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate

Under an argon stream, N,N-dimethylacetamide (351 ml, 5.0 v/w) was addedto methyl4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate(70.3 g, 0.134 mol) obtained in Example 1(5) and potassium carbonate(73.9 g, 0.535 mol) was carefully added with stirring. After stirringthe mixture at room temperature for 20 min., dimethyl sulfate (50.6 ml,0.535 mol) was added. After stirring at 50° C. for 1 hr., potassiumcarbonate (18.4 g, 0.134 mol) and dimethyl sulfate (12.7 ml, 0.134 mol)were added and the mixture was stirred at 60° C. for 2 hr. After coolingto room temperature, n-hexane (422 ml, 6.0 v/w) was added, and themixture was stirred for 1 hr. After ice-cooling, distilled water (562ml, 8.0 v/w) was added. After stirring at room temperature for 1 hr.,the resulting crystals were collected by filtration and washed withmethanol (352 ml, 5.0 v/w) in a slurry form. Tetrahydrofuran (180 ml)was added to the obtained orange solid and insoluble materials werefiltered off. The filtrate was concentrated to give the title compound(42.1 g, yield 58.3%) as a pale-yellow solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 1.16-1.47(5H,m), 1.65-1.80(5H,m),2.40-2.55(1H,m), 3.01(3H,s), 3.07(3H,s), 3.83(3H,s), 4.54(2H,s),4.81(2H,s), 6.71(2H,d,J=8.9 Hz), 6.84(1H,s), 7.08-7.16(4H,m),7.46(2H,d,J=8.3 Hz), 7.62(2H,d,J=8.8 Hz), 7.94(2H,d,J=8.3 Hz).

(7)4-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoicacid

Under an argon stream, tetrahydrofuran (202 ml, 5.0 v/w) and methanol(102 ml, 3.0 v/w) were added to methyl4-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate(40.7 g, 75.4 mmol) obtained in Example 1 (6). With stirring at 50° C.,a 1N-aqueous sodium hydroxide solution (151 ml, 151 mmol) was added.After stirring at 60° C. for 1 hr., distilled water (173 ml, 4.25 v/w)was added. With stirring, 2N-hydrochloric acid (75.4 ml, 151 mmol) wascarefully added. After stirring for 1 hr., the resulting crystals werecollected by filtration and washed successively with distilled water(407 ml) and ethanol (204 ml), and dried in vacuo to give a yellow solid(39.2 g).

Tetrahydrofuran (172 ml, 4.5 v/w) was added to the obtained yellow solid(38.2 g) and the mixture was stirred at 50° C. for 1 hr. Afterfiltration, the residue was washed with tetrahydrofuran (19 ml, 0.5v/w). Ethanol (134 ml, 3.5 v/w) and distilled water (134 ml, 3.5 v/w)were successively added to the filtrate with stirring at 50° C. and themixture was stirred at 50° C. for 1 hr. and at room temperature for 1hr. The resulting crystals were collected by filtration, washed withethanol (306 ml) and dried in vacuo to give the title compound (36.5 g,yield 91.9%) as a pale-yellow solid.

¹H-NMR(300 MHz,DMSO-d₆) δ 1.16-1.47(5H,m), 1.65-1.80(5H,m),2.40-2.55(1H,m), 3.01(3H,s), 3.07(3H,s), 4.54(2H,s), 4.81(2H,s),6.71(2H,d,J=9.0 Hz), 6.83(1H,s), 7.08-7.16(4H,m), 7.43(2H,d,J=8.4 Hz),7.63(2H,d,J=8.8 Hz), 7.92(2H,d,J=8.2 Hz), 12.85(1H,brs).

melting point: 180-181° C.

EXAMPLE 2 potassium4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate(1) 4-(4-cyclohexylbenzyloxy)acetophenone

Toluene (225 ml) and 48% hydrobromic acid (150 ml) were added to4-cyclohexylbenzyl alcohol (74.9 g, 0.394 mol) and the mixture wasstirred at 50° C. for 14 hr. After partitioning, the organic layer waswashed successively with water (100 ml), saturated aqueous sodiumhydrogen carbonate (100 ml), water (100 ml) and saturated brine, anddried over magnesium sulfate. After filtration and solvent evaporation,the residue was dried in vacuo to give a pale-yellow oil. The obtainedoil was dissolved in N,N-dimethylformamide (500 ml) and4-hydroxyacetophenone (50.3 g, 0.369 mol) and potassium carbonate (153g, 1.11 mol) were added. The mixture was stirred at 45° C. for 70 min.After ice-cooling, water (750 ml) was added dropwise and the mixture wasstirred at room temperature for 30 min. The precipitated crystals werecollected by filtration, washed with water, washed with n-hexane anddried to give the title compound (93.5 g, yield 86.6%).

¹H-NMR(400 MHz,DMSO-d₆) δ 1.15-1.52(5H,m), 1.58-1.87(5H,m), 2.47(1H,m),2.51(3H,s), 5.15(2H,s), 7.10(2H,d,J=9.3 Hz), 7.24(2H,d,J=8.4 Hz),7.36(2H,d,J=8.4 Hz), 7.92(2H,d,J=9.3 Hz).

(2) 2′-bromo-4-(4-cyclohexylbenzyloxy)acetophenone

To a suspension of 4-(4-cyclohexylbenzyloxy)acetophenone (60.0 g, 0.195mol) obtained in Example 2(1) in 1,2-dimethoxyethane (480 ml) was addeddropwise a solution of bromine (10.5 ml, 0.205 mol) in1,2-dimethoxyethane (120 ml) at room temperature. After stirring at roomtemperature for 90 min., water (600 ml) was added dropwise underice-cooling, and the mixture was stirred at room temperature for 30 min.The precipitated crystals were collected by filtration, washed withwater, washed with n-heptane and dried to give the title compound (68.2g, yield 90.1%).

¹H-NMR(400 MHz,CDCl₃) δ 1.18-1.50(5H,m), 1.70-1.95(5H,m), 2.51(1H,m),4.38(2H,s), 5.10(2H,s), 7.03(2H,d,J=8.9 Hz), 7.24(2H,d,J=8.4 Hz),7.34(2H,d,J=8.4 Hz), 7.96(2H,d,J=8.9 Hz).

(3) methyl4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylaminomethyl)benzoate

Acetonitrile (630 ml) was added to1-(4-methoxycarbonylbenzyl)-2-thiourea (33.0 g, 0.147 mol) obtained inExample 1(1), 2′-bromo-4-(4-cyclohexylbenzyloxy)acetophenone (62.7 g,0.162 mol) obtained in Example 2(2) and sodium bicarbonate (13.6 g,0.162 mol), and the mixture was heated under reflux for 4 hr. Aftercooling to room temperature, water (630 ml) was added and the mixturewas stirred at the same temperature for 1 hr. The precipitated crystalswere collected by filtration, washed successively with 50% acetonitrile(130 ml), water (2 L) and diisopropyl ether (500 ml) and dried to givethe title compound (76.4 g, quant.).

¹H-NMR(400 MHz,DMSO-d₆) δ 1.16-1.47(5H,m), 1.65-1.80(5H,m), 2.50(1H,m),3.84(3H,s), 4.61(2H,brs), 5.06(2H,s), 6.91(1H,s), 7.00(2H,d,J=8.9 Hz),7.23(2H,d,J=8.1 Hz), 7.35(2H,d,J=8.1 Hz), 7.53(2H,d,J=8.1 Hz),7.70(2H,d,J=8.9 Hz), 7.94(2H,d,J=8.1 Hz), 8.28-8.52(1H,brs).

(4) methyl4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate

Under an argon atmosphere, a suspension of methyl4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylaminomethyl)benzoate(65.0 g, 0.127 mol) obtained in Example 2(3) in N,N-dimethylformamide(130 ml) and dimethyl sulfate (15.0 ml, 0.159 mol) were successivelyadded dropwise to a suspension of sodium hydride (content 60%, 6.09 g,0.152 mol) in N,N-dimethylformamide (130 ml) at 10° C. or below and themixture was stirred at room temperature for 1 hr. Diisopropyl ether (195ml) and water (130 ml) were successively added dropwise at 10° C. orbelow, and the mixture was stirred at room temperature for 30 min. Theprecipitated crystals were collected by filtration, washed successivelywith diisopropyl ether (195 ml) and water (130 ml) and dried to give thetitle compound (56.0 g, 83.7%).

¹H-NMR(400 MHz,DMSO-d₆) δ 1.16-1.47(5H,m), 1.65-1.86(5H,m), 2.50(1H,m),3.09(3H,s), 3.84(3H,s), 4.83(2H,s), 5.06(2H,s), 7.00(2H,d,J=8.9 Hz),7.01(1H,s), 7.23(2H,d,J=8.1 Hz), 7.35(2H,d,J=8.1 Hz), 7.46(2H,d,J=8.1Hz), 7.76(2H,d,J=8.9 Hz), 7.94(2H,d,J=8.1 Hz).

(5)4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoicacid

Tetrahydrofuran (250 ml), methanol (250 ml) and a 2N-aqueous sodiumhydroxide solution (95.0 ml, 190 mmol) were added to methyl4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate(50.0 g, 94.9 mmol) obtained in Example 2(4), and the mixture was heatedunder reflux for 40 min under an argon atmosphere. Water (310 ml) wasadded to the reaction mixture and the mixture was cooled to roomtemperature. 2N-Hydrochloric acid (95.0 ml, 190 mmol) was added dropwiseand the mixture was stirred for 90 min. The resulting crystals werecollected by filtration, washed with water (700 mL) and dried to givethe title compound (48.5 g, yield 99.7%).

¹H-NMR(400 MHz,DMSO-d₆) δ 1.15-1.47(5H,m), 1.64-1.85(5H,m), 2.47(1H,m),3.09(3H,s), 4.82(2H,s), 5.06(2H,s), 7.00(2H,d,J=9.2 Hz), 7.02(1H,s),7.23(2H,d,J=8.4 Hz), 7.35(2H,d,J=8.4 Hz), 7.42(2H,d,J=8.1 Hz),7.77(2H,d,J=9.2 Hz), 7.92(2H,d,J=8.1 Hz).

(6) potassium4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate

Under an argon atmosphere, to a suspension of4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoicacid (30.0 g, 58.5 mmol) obtained in Example 2(5) was added 1N aqueouspotassium hydroxide solution (56.0 ml) at 50° C. and the mixture washeated under reflux for 40 min. After stirring at room temperature for45 min., the crystals were collected by filtration, washed with atetrahydrofuran-ethanol mixed solvent (3:1, 150 ml) and ethanol (210ml), and dried to give the title compound (28.0 g, yield 90.9%).

¹H-NMR(400 MHz, DMSO-d₆) δ 1.17-1.47(5H, m), 1.65-1.84(5H, m), 2.50(1H,m), 3.04(3H,s), 4.71(2H,s), 5.07(2H,s), 6.99(1H,s), 7.00(2H,d,J=8.9 Hz),7.19(2H,d,J=8.1 Hz), 7.23(2H,d,J=8.1 Hz), 7.36(2H,d,J=8.1 Hz),7.77(2H,d,J=8.9 Hz), 7.79(2H,d,J=8.1 Hz).

melting point: 288-291° C. (dec.)

EXAMPLE 34-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoicacid (1) ethyl 4-((4-(4-nitrophenyl)-2-thiazolyl)amino)benzoatehydrobromide

A solution of 2′-bromo-4-nitroacetophenone (87.1 g, 0.357 mol) and1-(4-ethoxycarbonylphenyl)-2-thiourea (80.0 g, 0.357 mol) inacetonitrile (1.6 L) was heated under reflux for 1 hr under an argonatmosphere. After cooling to room temperature, the resulting crystalswere collected by filtration and dried to give the title compound (153g, yield 94.9%).

¹H-NMR(400 MHz, DMSO-d₆) δ 1.33(3H,t,J=7.1 Hz), 4.29(2H,q,J=7.1 Hz),7.84(1H,s), 7.87(2H,d,J=9.1 Hz), 7.97(2H,d,J=8.6 Hz), 8.22(2H,d,J=8.6Hz), 8.27(2H,d,J=9.2 Hz), 10.82(1H,s).

(2) ethyl 4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)amino)benzoate

Under a nitrogen stream, N,N-dimethylformamide (1.05 L, 7.0 v/w) wasadded to ethyl 4-((4-(4-nitrophenyl)-2-thiazolyl)amino)benzoatehydrobromide (150 g, 0.333 mol) obtained in Example 3(1). With stirringunder ice-cooling, potassium carbonate (138 g, 0.999 mol) was addedcarefully. After stirring at room temperature for 20 min., dimethylsulfate (63.2 ml, 0.666 mol) was added. After stirring at 60° C. for 2hr., distilled water (1.05 L, 7.0 v/w) was added with stirring underice-cooling. After stirring under ice-cooling for 1 hr., the resultingcrystal were collected by filtration, washed with distilled water (450mL) and dried in vacuo to give the title compound (127 g, yield 99.3%)as an orange crystal.

¹H-NMR(400 MHz,DMSO-d₆) δ 1.34(3H,t,J=7.1 Hz), 3.62(3H,s),4.33(2H,q,J=7.1 Hz), 7.74(2H,d,J=8.8 Hz), 7.78(1H,s), 8.03(2H,d,J=8.8Hz), 8.14(2H,d,J=9.0 Hz), 8.28(2H,d,J=9.0 Hz).

(3) ethyl 4-(N-(4-(4-aminophenyl)-2-thiazolyl)-N-methylamino)benzoate

Under a nitrogen stream, N,N-dimethylformamide (1.20 L, 10.0 v/w) wasadded to ethyl4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)amino)benzoate (123 g,0.321 mol) obtained in Example 3(2). With stirring at room temperature,sodium hydrosulfite (80% purity, 210 g, 0.963 mol) was added. Afterstirring at room temperature for 10 min., distilled water (123 ml, 1.0v/w) was added carefully. After stirring at 100° C. for 1.5 hr.,triethylamine (223 ml, 1.61 mol) was added at 80° C., and the mixturewas cooled to room temperature with water. After stirring at roomtemperature for 1 hr., distilled water (1.1 L, 9.0 v/w) was added. Afterstirring at room temperature for 30 min., the mixture was extractedtwice with ethyl acetate (1.20 L) and the organic layer was washedsuccessively with distilled water (400 ml) and saturated brine (400 ml),and dried over magnesium sulfate (60 g). The magnesium sulfate wasfiltered off, the solvent was evaporated, the residue was boiled withtoluene and dried in vacuo to give the title compound (67.0 g, yield63.0%) as a yellow to orange solid.

¹H-NMR(400 MHz,DMSO-d₆) δ 1.33(3H,t,J=7.0 Hz), 3.57(3H,s),4.32(2H,q,J=7.0 Hz), 5.27(2H,brs), 6.59(2H,d,J=8.6 Hz), 7.02(1H,s),7.56(2H,d,J=8.6 Hz), 7.71(2H,d,J=9.0 Hz), 7.99(2H,d,J=9.0 Hz).

(4) ethyl4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoate

Under a nitrogen stream, tetrahydrofuran (306 ml, 6.0 v/w) was added toethyl 4-(N-(4-(4-aminophenyl)-2-thiazolyl)-N-methylamino)benzoate (51.0g, 0.144 mol) obtained in Example 3(3). With stirring at roomtemperature, a solution of 4-cyclohexylbenzaldehyde (30.0 g, 0.158 mol)obtained in Production Example 1(2) in tetrahydrofuran (153 ml, 3.0 v/w)was added. The mixture was washed with tetrahydrofuran (51 ml, 1.0 v/w)and stirred at room temperature for 30 min. With stirring underice-cooling, sodium triacetoxyborohydride (46.0 g, 0.216 mol) and aceticacid (12.4 ml, 0.216 mol) were added, and the mixture was stirred atroom temperature for 1.5 hr. With stirring under ice-cooling, saturatedaqueous sodium hydrogen carbonate (510 ml, 10.0 v/w) was addedcarefully. After stirring at room temperature for 1 hr., the mixture wasextracted with ethyl acetate (408 ml) and the organic layer was washedsuccessively with distilled water (255 ml) and saturated brine (255 ml),and dried over magnesium sulfate (50 g). After filtration and solventevaporation, isopropyl alcohol (510 ml, 10.0 v/w) was added to theobtained orange solid, and the mixture was stirred at 60° C. for 1 hr.After stirring under ice-cooling for 1 hr., the resulting crystal werecollected by filtration, and washed with isopropyl alcohol (102 ml) andtert-butylmethyl ether (102 ml) and dried in vacuo to give the titlecompound (58.0 g, yield 77.0%) as a pale-yellow solid.

¹H-NMR(400 MHz,DMSO-d₆) δ 1.23-1.40(8H, m,), 1.67-1.78(5H,m),2.46(1H,s), 3.56(3H,s), 4.24(2H,d,J=6.1 Hz), 4.31(2H,q,J=7.1 Hz),6.35(1H,t,J=6.1 Hz), 6.60(2H,d,J=8.6 Hz), 7.01(1H,s), 7.16(2H,d,J=7.6Hz), 7.27(6H,d,J=7.6 Hz), 7.57(2H,d,J=8.6 Hz), 7.70(2H,d,J=8.9 Hz),7.98(2H,d,J=8.9 Hz).

(5)4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoicacid

Under a nitrogen stream, tetrahydrofuran (312 ml, 6.0 v/w) and methanol(104 ml, 2.0 v/w) were added to ethyl4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoate(52.0 g, 98.9 mmol) obtained in Example 3(4). With stirring underice-cooling, 2N-aqueous sodium hydroxide solution (98.9 ml, 197.8 mmol)was added. After stirring at 60° C. for 2 hr., distilled water (104 ml,2.0 v/w) was added. With stirring under ice-cooling, 2N-hydrochloricacid (98.9 ml, 197.8 mmol) was added carefully. After stirring underice-cooling for 1 hr., the resulting crystal were collected byfiltration, washed with distilled water (156 ml) and dried in vacuo togive a yellow solid (51.9 g). Tetrahydrofuran (750 ml, 15.0 v/w) wasadded to the obtained yellow solid (50.0 g) and the mixture was stirredat 60° C. for 1 hr. After allowing to cool to room temperature, theprecipitate was collected by filtration and washed with tetrahydrofuran(100 ml, 2.0 v/w). With stirring at room temperature, ethanol (150 ml)and distilled water (150 ml) were successively added to the filtrate.After stirring under ice-cooling for 1 hr., the resulting crystals werecollected by filtration, washed successively with distilled water (200ml) and 50% aqueous ethanol (200 ml) and dried in vacuo to give a crudetitle compound (33.6 g) as a yellow solid. Ethanol (350 ml, 7.0 v/w) wasadded and the mixture was stirred at room temperature for 2 hr. Theresulting crystals were collected by filtration, washed with ethanol(200 ml) and dried in vacuo to give the title compound (32.1 g, yield64.2%) as a pale-yellow solid.

¹H-NMR(400 MHz,DMSO-d₆) δ 1.20-1.40(5H,m), 1.67-1.78(5H,m), 2.43(1H,m),3.56(1H,s), 4.23(3H,d,J=5.1 Hz), 6.34(1H,brt,J=5.1 Hz), 6.60(2H,d,J=8.6Hz), 6.98(1H,s), 7.16(2H,d,J=8.1 Hz), 7.27(2H,d,J=8.1 Hz),7.57(2H,d,J=8.6 Hz), 7.67(2H,d,J=8.9 Hz), 7.97(2H,d,J=8.9 Hz).

melting point: 252-253° C. (dec.)

The following compounds were produced according to a method similar tothe methods of Examples 1-3, and using a conventional method wherenecessary.

-   4-(4-(4-benzoylaminophenyl)-2-thiazolylamino)benzoic acid (Example    4),-   4-(4-(4-(4-tert-butylbenzoylamino)phenyl)-2-thiazolylamino)benzoic    acid (Example 5),-   4-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolylamino)benzoic    acid (Example 6),-   4-(N-(4-(4-benzoylaminophenyl)-2-thiazolyl)-N-ethylamino)benzoic    acid (Example 7),-   4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-ethylamino)benzoic    acid (Example 8),-   4-(N-(4-(4-benzoylaminophenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 9),-   4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 10),-   4-(N-(4-(4-(cyclohexanecarbonylamino)phenyl)-2-thiazolyl)-N-ethylamino)benzoic    acid (Example 11),-   4-(N-(4-(4-(cyclohexanecarbonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 12),-   4-(N-(4-(4-(cyclohexanecarbonylamino)phenyl)-2-thiazolyl)-N-isobutylamino)benzoic    acid (Example 13),-   4-(N-carboxymethyl-N-(4-(4-(cyclohexanecarbonylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 14),-   4-(N-(4-(4-benzoylaminophenyl)-2-thiazolyl)-N-isobutylamino)benzoic    acid (Example 15),-   4-(N-(4-(4-benzoylaminophenyl)-2-thiazolyl)-N-carboxymethylamino)benzoic    acid (Example 16),-   4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isobutylamino)benzoic    acid (Example 17),-   4-(N-carboxymethyl-N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 18),-   4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 19),-   4-(N-(4-(4-(4-tert-butylbenzoylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 20),-   4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylamino)benzoic acid    (Example 21),-   4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 22),-   4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-ethylamino)benzoic    acid (Example 23),-   4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 24),-   4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 25),-   4-(N-(3-carboxypropyl)-N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 26),-   3-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolylamino)benzoic    acid (Example 27),-   3-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 28),-   4-(N-isopropyl-N-(4-(4-(4-morpholinobenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 29),-   3-(N-isopropyl-N-(4-(4-(4-piperidinobenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 30),-   3-(N-isopropyl-N-(4-(4-(4-morpholinobenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 31),-   4-(N-isopropyl-N-(4-(4-(4-piperidinobenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 32),-   4-(N-isopropyl-N-(4-(4-(4-(4-methylpiperidino)benzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 33),-   sodium    4-(N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)benzoate    (Example 34),-   4-(N-(4-(4-(4-(3,5-dimethylpiperidino)benzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid hydrochloride (Example 35),-   cis-4-(N-(4-(4-(4-(2,6-dimethylmorpholino)benzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid hydrochloride (Example 36),-   sodium    4-(N-isopropyl-N-(4-(4-(4-(4-methyl-1-piperazinyl)benzoylamino)phenyl)-2-thiazolyl)amino)benzoate    (Example 37),-   2-chloro-4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 38),-   2-chloro-4-(N-isopropyl-N-(4-(4-(4-piperidinobenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 39),-   2-chloro-4-(N-isopropyl-N-(4-(4-(4-morpholinobenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 40),-   2-chloro-4-(N-isopropyl-N-(4-(4-(4-(4-methyl-1-piperazinyl)benzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 41),-   4-(1-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-1-methylethyl)benzoic    acid (Example 42),-   4-(1-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-1-methylethyl)benzoic    acid (Example 43),-   4-(1-methyl-1-(4-(4-(4-morpholinobenzoylamino)phenyl)-2-thiazolyl)ethyl)benzoic    acid (Example 44),-   4-(1-methyl-1-(4-(4-(4-piperidinobenzoylamino)phenyl)-2-thiazolyl)ethyl)benzoic    acid (Example 45),-   4-(N-(4-(4-(4-cyclohexylbutyrylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 46),-   4-(4-(4-(4-tert-butylbenzyloxy)phenyl)-2-thiazolylmethyl)benzoic    acid (Example 47),-   4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylmethyl)benzoic    acid (Example 48),-   4-(4-(4-(4-carboxybenzyloxy)phenyl)-2-thiazolylmethyl)benzoic acid    (Example 49),-   (4-(N-(4-(4-(cyclohexanecarbonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)phenoxy)acetic    acid (Example 50),-   (4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)phenoxy)acetic    acid (Example 51),-   4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)-2,3,5,6-tetrafluorobenzoic    acid (Example 52),-   (4-(N-isopropyl-N-(4-(4-(4-piperidinobenzoylamino)phenyl)-2-thiazolyl)amino)phenoxy)acetic    acid (Example 53),-   (4-(N-isopropyl-N-(4-(4-(4-morpholinobenzoylamino)phenyl)-2-thiazolyl)amino)phenoxy)acetic    acid (Example 54),-   (4-(N-(4-(4-(3,5-bis(trifluoromethyl)benzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)phenoxy)acetic    acid (Example 55),-   (4-(N-(4-(4-(3,5-dichlorobenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)phenoxy)acetic    acid (Example 56),-   (4-(N-isopropyl-N-(4-(4-(2-piperidino-5-pyridinecarbonylamino)phenyl)-2-thiazolyl)amino)phenoxy)acetic    acid (Example 57),-   4-(N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 58),-   4-(N-cyclohexylmethyl-N-(4-(4-(4-trifluoromethylbenzoylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 59),-   4-(N-(4-(4-(N-(4-cyclohexylbenzoyl)-N-methylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 60),-   4-((N-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 61),-   4-((N-isopropyl-N-(4-(4-(4-piperidinobenzoylamino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 62),-   4-((N-isopropyl-N-(4-(4-(4-morpholinobenzoylamino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 63),-   4-((N-(4-(4-(4-biphenylcarbonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 64),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 65),-   4-(2-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)ethyl)benzoic    acid (Example 66),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 67),-   4-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolylmethyl)benzoic    acid (Example 68),-   4-(4-(4-(4-isopropoxybenzoylamino)phenyl)-2-thiazolylmethyl)benzoic    acid (Example 69),-   4-(4-(4-(4-(1-pyrrolyl)benzoylamino)phenyl)-2-thiazolylmethyl)benzoic    acid (Example 70),-   4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolecarbonyl)benzoic    acid (Example 71),-   4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylamino)-3-(2-cyclohexylethoxy)benzoic    acid (Example 72),-   3-benzyloxy-4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylamino)benzoic    acid (Example 73),-   3-(4-carboxybenzyloxy)-4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylamino)benzoic    acid (Example 74),-   4-cyclohexyl-N-(4-(2-(N-isopropyl-N-(4-(1H-tetrazol-5-yl)phenyl)amino)-4-thiazolyl)phenyl)benzamide    (Example 75),-   3-(2-(4-(4-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)ethyl)benzoic    acid (Example 76),-   4-((N-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 77),-   N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropyl-(4-(1H-tetrazol-5-yl)phenyl)amine    (Example 78),-   N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropyl-(4-(1H-tetrazol-5-yl)benzyl)amine    (Example 79),-   N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropyl-(3-(1H-tetrazol-5-yl)benzyl)amine    (Example 80),-   4-((4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylamino)methyl)benzoic    acid (Example 81),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 82),-   4-((N-(4-(4-(4-(4-fluorophenyl)-2-methyl-5-thiazolylmethoxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 83),-   4-((N-(4-(4-(4′-chloro-4-methoxybiphenyl-2-ylmethoxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 84),-   4-((N-isopropyl-N-(4-(4-(4-methyl-2-(4-trifluoromethylphenyl)-5-thiazolylmethoxy)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 85),-   N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropyl-(2-(1H-tetrazol-5-yl)benzyl)amine    (Example 86),-   3-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 87),-   2-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 88),-   4-(N-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 89),-   4-(1-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-1-methylethyl)benzoic    acid (Example 90),-   4-(1-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)cyclopentyl)benzoic    acid (Example 91),-   4-(1-(4-(4-(4-biphenylylmethoxy)phenyl)-2-thiazolyl)-1-methylethyl)benzoic    acid (Example 92),-   4-(1-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)cyclohexyl)benzoic    acid (Example 93),-   4-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolylamino)benzoic acid    (Example 94),-   4-(4-(4-(4-biphenylylmethoxy)phenyl)-2-thiazolylamino)benzoic acid    (Example 95),-   4-(N-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 96),-   4-(N-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-(2-dimethylaminoethyl)amino)benzoic    acid (Example 97),-   4-(N-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-(2-piperidinoethyl)amino)benzoic    acid (Example 98),-   4-(N-(4-(4-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-(2-methoxyethyl)amino)benzoic    acid (Example 99),-   4-(1-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)cyclohexyl)benzoic    acid (Example 100),-   4-(4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)tetrahydropyran-4-yl)benzoic    acid (Example 101),-   sodium    4-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoate    (Example 102),-   4-((N-isopropyl-N-(4-(4-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 103),-   4-((N-(4-(4-(4-tert-butylbenzenesulfonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 104),-   4-((N-(4-(4-(3,4-dichlorobenzenesulfonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 105),-   4-((N-isopropyl-N-(4-(4-(4-trifluoromethylbenzenesulfonylamino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 106),-   4-((N-(4-(4-(4-cyclohexylbenzenesulfonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 107),-   4-((N-(4-(4-(4-cyclohexylbenzylsulfanyl)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 108),-   4-((N-(4-(4-dibenzylaminophenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 109),-   4-((N-(4-(4-(N-(4-cyclohexylbenzenesulfonyl)-N-methylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 110),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-propylamino)methyl)benzoic    acid (Example 111),-   4-((N-(4-(4-(4-cyclohexylphenylmethanesulfonyl)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 112),-   4-((N-benzyl-N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 113),-   4-((N-(4-(4-(N-benzyl-N-(4-cyclohexylbenzyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 114),-   4-((N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 115),-   4-((N-cyclohexylmethyl-N-(4-(4-(3,4-dichlorobenzylamino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 116),-   4-((N-(4-(4-(bis(3,4-dichlorobenzyl)amino)phenyl)-2-thiazolyl)-N-cyclohexylmethylamino)methyl)benzoic    acid (Example 117),-   4-((N-cyclohexylmethyl-N-(4-(4-(N-(3,4-dichlorobenzyl)-N-methylamino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 118),-   4-((N-(4-(4-(N-allyl-N-(4-cyclohexylbenzyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 119),-   sodium    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 120),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid N-methyl-D-glucamine salt (Example 121),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid tris(hydroxymethyl)aminomethane salt (Example 122),-   4-((N-(4-(4-(N-benzyl-N-cyclohexylmethylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 123),-   4-((N-(4-(4-(N-cyclohexylmethyl-N-(4-trifluoromethylbenzyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 124),-   sodium    4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolecarbonyl)benzoate    (Example 125),-   potassium    4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolecarbonyl)benzoate    (Example 126),-   4-((N-isopropyl-N-(4-(4-(3-piperidinobenzyloxy)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid dihydrochloride (Example 127),-   4-(N-(4-(4-(3,4-dichlorobenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 128),-   4-(N-cyclohexylmethyl-N-(4-(4-(3,4-dichlorobenzylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 129),-   4-(N-cyclohexylmethyl-N-(4-(4-(4-isopropylbenzylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 130),-   4-(N-cyclohexylmethyl-N-(4-(4-(4-isobutylbenzylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 131),-   4-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 132),-   4-(N-methyl-N-(4-(4-(4-trifluoromethylbenzylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 133),-   4-(N-cyclohexylmethyl-N-(4-(4-(4-trifluoromethylbenzylamino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 134),-   4-((N-(4-(4-(N-cyclohexylmethyl-N-(4-trifluoromethylbenzyl)amino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 135),-   4-((N-isopropyl-N-(4-(4-(N-(tetrahydropyran-4-ylmethyl)-N-(4-trifluoromethylbenzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 136),-   4-(N-methyl-N-(4-(4-(N-methyl-N-(4-trifluoromethylbenzyl)amino)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 137),-   4-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylamino)benzoic acid    (Example 138),-   4-(N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 139),-   4-(N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-ethylamino)benzoic    acid (Example 140),-   4-(N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 141),-   4-(N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 142),-   4-((N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 143),-   4-((N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 144),-   4-((N-(4-(3-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-cyclohexylmethylamino)methyl)benzoic    acid (Example 145),-   4-((N-(4-(3-(4-cyclohexylbenzoylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 146),-   4-((N-(4-(3-(4-cyclohexylbenzenesulfonylamino)phenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 147),-   4-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolylamino)benzoic acid    (Example 148),-   4-(1-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-1-methylethyl)benzoic    acid (Example 149),-   4-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolylamino)-3-(2-cyclohexylethoxy)benzoic    acid (Example 150),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-methylamino)benzoic    acid (Example 151),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 152),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(2-phenoxyethyl)amino)benzoic    acid (Example 153),-   4-(4-(2-benzyloxy-5-methoxyphenyl)-2-thiazolylamino)benzoic acid    (Example 154),-   4-(4-(5-methoxy-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolylamino)benzoic    acid (Example 155),-   3-benzyloxy-4-(4-(2-benzyloxy-5-methoxyphenyl)-2-thiazolylamino)benzoic    acid (Example 156),-   4-(4-(2-(4-cyclohexylbenzyloxy)-5-methoxyphenyl)-2-thiazolylamino)benzoic    acid (Example 157),-   5-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolylmethyl)-2-hydroxybenzoic    acid (Example 158),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(4-trifluoromethylbenzyl)amino)benzoic    acid (Example 159),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 160),-   4-((N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 161),-   4-((4-(2-benzyloxy-5-chlorophenyl)-2-thiazolylamino)methyl)benzoic    acid (Example 162),-   4-((N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 163),-   4-((N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)methyl)benzoic    acid (Example 164),-   4-((N-(4-(5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)methyl)benzoic    acid (Example 165),-   4-((N-(2-cyclohexylethyl)-N-(4-(5-methoxy-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 166),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(3,4-dichlorobenzyl)amino)benzoic    acid (Example 167),-   4-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(3-methylbutyl)amino)benzoic    acid (Example 168),-   4-(N-(4-(2-benzyloxy-5-methoxyphenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 169),-   4-(N-(2-cyclohexylethyl)-N-(4-(5-methoxy-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 170),-   3-(2-cyclohexylethoxy)-4-(4-(5-methoxy-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolylamino)benzoic    acid (Example 171),-   3-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 172),-   4-(4-(5-chloro-2-(4-isopropylbenzyloxy)phenyl)-2-thiazolylamino)benzoic    acid (Example 173),-   4-(N-(4-(2-benzyloxy-5-fluorophenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 174),-   4-(N-(4-(2-benzyloxy-5-methylphenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 175),-   4-(N-(4-(5-chloro-2-(4-isopropylbenzyloxy)phenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 176),-   4-(N-(4-(5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 177),-   4-(N-(4-(5-chloro-2-(3,4-dichlorobenzyloxy)phenyl)-2-thiazolyl)-N-(2-cyclohexylethyl)amino)benzoic    acid (Example 178),-   4-(4-(5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolylamino)-3-(2-cyclohexylethoxy)benzoic    acid (Example 179),-   3-benzyloxy-4-(4-(5-methoxy-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolylamino)benzoic    acid (Example 180),-   3-(N-(4-(2-benzyloxy-5-chlorophenyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 181),-   4-(N-butyl-N-(4-(5-chloro-2-(4-trifluoromethylbenzyloxy)phenyl)-2-thiazolyl)amino)benzoic    acid (Example 182),-   4-(N-(4-(6-(3,4-dichlorobenzyloxy)-2-benzooxazolyl)-2-thiazolyl)-N-isopropylamino)benzoic    acid (Example 183),-   4-(N-(2-cyclohexylethyl)-N-(4-(6-(3,4-dichlorobenzyloxy)-2-benzooxazolyl)-2-thiazolyl)amino)benzoic    acid (Example 184),-   4-(N-(2-cyclohexylethyl)-N-(4-(5-(3,4-dichlorobenzyloxy)-2-benzoimidazolyl)-2-thiazolyl)amino)benzoic    acid hydrochloride (Example 185),-   4-(4-(5-(3,4-dichlorobenzyloxy)-2-benzoimidazolyl)-2-thiazolylamino)benzoic    acid hydrochloride (Example 186),-   4-(N-cyclohexylmethyl-N-(4-(6-(3,4-dichlorobenzyloxy)-2-benzooxazolyl)-2-thiazolyl)amino)benzoic    acid (Example 187),-   4-(N-(4-(6-(4-tert-butylbenzyloxy)-2-benzooxazolyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 188),-   4-(N-(4-(6-(2,4-bis(trifluoromethyl)benzyloxy)-2-benzooxazolyl)-2-thiazolyl)-N-cyclohexylmethylamino)benzoic    acid (Example 189),-   4-(N-cyclohexylmethyl-N-(4-(6-(3,4-difluorobenzyloxy)-2-benzooxazolyl)-2-thiazolyl)amino)benzoic    acid (Example 190),-   4-(N-cyclohexylmethyl-N-(4-(6-(3,5-dimethoxybenzyloxy)-2-benzooxazolyl)-2-thiazolyl)amino)benzoic    acid (Example 191),-   4-((N-(4-(4-cyclopentyloxyphenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid (Example 192),-   4-((N-(4-(4-dicyclohexylmethoxyphenyl)-2-thiazolyl)-N-isopropylamino)methyl)benzoic    acid hydrochloride (Example 193),-   cis-4-((N-(4-(4-(N-(4-(4-hydroxycyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 194),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-(4-oxocyclohexyl)benzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 195),-   trans-4-((N-(4-(4-(N-(4-(4-hydroxycyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 196),-   4-((N-(4-(3-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 197),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-(2-methoxyacetyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 198),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-(2-hydroxyacetyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 199),-   sodium    4-((N-(4-(3-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 200),-   4-((N-(4-(3-(N-acetyl-N-(4-cyclohexylbenzyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 201),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methanesulfonylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 202),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-(2-hydroxyethyl)amino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 203),-   3-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 204),-   cis-4-((N-(4-(4-(N-(4-(3-hydroxycyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 205),-   trans-4-((N-(4-(4-(N-(4-(3-hydroxycyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 206),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-(3-oxocyclohexyl)benzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 207),-   4-((N-(4-(4-(N-(4-(4,4-dichlorocyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 208),-   4-((N-(4-(4-(N-(4-(4,4-difluorocyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 209),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-(tetrahydropyran-4-yl)benzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 210),-   4-((N-(4-(4-(N-(4-(1-acetylpiperidin-4-yl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 211),-   4-((N-(4-(4-(N-(4-cyclopentylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 212),-   trans-4-((N-methyl-N-(4-(4-(N-methyl-N-(4-phenylcyclohexylmethyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 213),-   cis-4-((N-methyl-N-(4-(4-(N-methyl-N-(4-phenylcyclohexylmethyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 214),-   4-((N-(4-(4-(N-(4-(4,4-dimethylcyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 215),-   sodium    4-((N-(4-(4-(N-(4-(4,4-dimethylcyclohexyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 216),-   4-((N-cyclohexylmethyl-N-(4-(6-(3,4-dichlorobenzyloxy)-2-benzooxazolyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 217),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-(4-methylcyclohexyl)benzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 218),-   4-((N-(4-(4-(N-(2-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 219),-   4-((N-(4-(6-benzyloxy-2-benzooxazolyl)-2-thiazolyl)-N-cyclohexylmethylamino)methyl)benzoic    acid (Example 220),-   4-((N-cyclohexylmethyl-N-(4-(6-phenethyloxy-2-benzooxazolyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 221),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-phenylbutyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 222),-   4-((N-(4-(4-(N-(2-(2-indanyl)ethyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 223),-   4-((N-(4-(4-(N-(2-(3,4-dichlorophenyl)ethyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 224),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(3-phenylpropyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 225),-   4-((N-(4-(6-(N-(4-cyclohexylbenzyl)-N-methylamino)-3-pyridyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 226),-   4-((N-(2′-(N-(4-cyclohexylbenzyl)-N-methylamino)-4′-methyl-4,5′-bithiazolyl-2-yl)-N-methylamino)methyl)benzoic    acid (Example 227),-   4-((N-(4-(2-chloro-6-(N-(4-cyclohexylbenzyl)-N-methylamino)-4-pyridyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 228),-   4-((N-(4-(4-(N-(4-(2,2-dimethylpropyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 229),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-(1-propylbutyl)benzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 230),-   4-((N-(4-(2-(4-cyclohexylphenyl)-1H-benzoimidazol-5-yl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 231),-   4-((N-(4-(5-chloro-6-(N-(4-cyclohexylbenzyl)-N-methylamino)-3-pyridyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 232),-   4-((N-(4-(4-(N-(4-tert-butylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 233),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(4-trifluoromethylbenzyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 234),-   4-((N-(4-(4-(N-(2-(4-tert-butylphenyl)ethyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 235),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(2-(4-trifluoromethylphenyl)ethyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 236),-   4-((N-(4-(4-(N-(2-(4-dimethylaminophenyl)ethyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 237),-   4-((N-methyl-N-(4-(4-(N-methyl-N-(2-(4-morpholinophenyl)ethyl)amino)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 238),-   4-((N-methyl-N-(4-(4-(4-phenyl-1-piperazinylmethyl)phenyl)-2-thiazolyl)amino)methyl)benzoic    acid (Example 239),-   4-((N-(4-(4-(4-benzyl-1-piperazinylmethyl)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 240),-   4-((N-(4-(4-(N-(4-(1-ethylpropyl)benzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 241),-   4-((N-(4-(3-chloro-4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 242),-   benzyl    4-(4-(2-(N-(4-carboxybenzyl)-N-methylamino)-4-thiazolyl)benzyl)-piperazine-1-carboxylate    (Example 243),-   4-((N-(4-(4-(N-(4-tert-butylbenzyl)-N-methylamino)-3-chlorophenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 244),-   4-((N-(4-(4-(N-(4-isobutylsulfanylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid (Example 245),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid lysine salt (Example 246),-   4-((4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolylamino)methyl)benzoic    acid (Example 247),-   3-oxo-1,3-dihydroisobenzofuran-1-yl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 248),-   ethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 249),-   1-acetoxyethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 250),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid methanesulfonate (Example 251),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid hydrochloride (Example 252),-   potassium    4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 253),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid hydrochloride (Example 254),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid methanesulfonate (Example 255),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid tris(hydroxymethyl)aminomethane salt (Example 256),-   4-((N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid sulfate (Example 257),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid hydrochloride (Example 258),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid methanesulfonate (Example 259),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid tris(hydroxymethyl)aminomethane salt (Example 260),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid N-methyl-D-glucamine salt (Example 261),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid sulfate (Example 262),-   sodium    4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoate    (Example 263),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid ½ sulfate (Example 264),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid histidine salt (Example 265),-   4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoic    acid lysine salt (Example 266),-   tert-butoxycarbonylmethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 267),-   2,2-dimethylpropionyloxymethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 268), 1-ethoxycarbonyloxyethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 269),-   acetoxymethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 270),-   1-isopropoxycarbonyloxyethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 271),-   1-cyclohexyloxycarbonyloxyethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 272),-   5-methyl-2-oxo-1,3-dioxl-4-ylmethyl    4-((N-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolyl)-N-methylamino)methyl)benzoate    (Example 273),-   4-(N-(4-(4-(4-cyclohexylbenzylamino)phenyl)-2-thiazolyl)-N-methylamino)benzoic    acid lysine salt (Example 274).

The structural formulas and property values of the compound of eachExample are shown in Tables 1 to 67. TABLE 1 Ex. Structural formula m.p.(° C.) 1

180-181 2

288-291 (dec.) 3

252-253 4

250 (dec.) 5

250 (dec.) 6

250 (dec.)

TABLE 2 Ex. Structural formula m.p. (° C.) 7

250 (dec.) 8

250 (dec.) 9

234-236

TABLE 3 Ex. Structural formula m.p. (° C.) 10

230 (dec.) 11

250 (dec.) 12

230 (dec.)

TABLE 4 Ex. Structural formula m.p. (° C.) 13

231-232 14

210 (dec.) 15

234-235

TABLE 5 Ex. Structural formula m.p. (° C.) 16

210 (dec.) 17

230 (dec.) 18

230 (dec.) 19

250 (dec.)

TABLE 6 Ex. Structural formula m.p. (° C.) 20

250 (dec.) 21

250 (dec.) 22

250 (dec.) 23

239-247

TABLE 7 Ex. Structural formula m.p. (° C.) 24

238-240 25

230 (dec.)

TABLE 8 Ex. Structural formula m.p. (° C.) 26

230 (dec.) 27

230 (dec.) 28

230 (dec.)

TABLE 9 Ex. Structural formula m.p. (° C.) 29

230 (dec.) 30

220 (dec.) 31

230 (dec.)

TABLE 10 Ex. Structural formula m.p. (° C.) 32

230 (dec.) 33

230 (dec.) 34

230 (dec.)

TABLE 11 Ex. Structural formula m.p. (° C.) 35

152-160 36

230 (dec.)

TABLE 12 Ex. Structural formula m.p. (° C.) 37

230 (dec.) 38

220 (dec.) 39

220 (dec.)

TABLE 13 Ex. Structural formula m.p. (° C.) 40

220 (dec.) 41

220 (dec.) 42

219-221 43

262-264

TABLE 14 Ex. Structural formula m.p. (° C.) 44

290 (dec.) 45

268-271 46

230 (dec.) 47

223-228 48

235-238 49

270 (dec.)

TABLE 15 Ex. Structural formula m.p. (° C.) 50

225 (dec.) 51

240 (dec.) 52

153-157 53

220 (dec.) 54

250 (dec.)

TABLE 16 Ex. Structural formula m.p. (° C.) 55

amorphous 56

192-194 57

237-240 58

amorphous 59

amorphous

TABLE 17 Ex. Structural formula m.p. (° C.) 60

amorphous 61

250 (dec.) 62

234 (dec.) 63

250 (dec.) 64

250 (dec.)

TABLE 18 Ex. Structural formula m.p. (° C.) 65

233-234 66

amorphous 67

amorphous 68

230 (dec.) 69

230 (dec.) 70

220 (dec.)

TABLE 19 Ex. Structural formula m.p. (° C.) 71

259-261 72

230 (dec.) 73

230 (dec.) 74

230 (dec.) 75

amorphous

TABLE 20 Ex. Structural formula m.p. (° C.) 76

amorphous 77

180-181 78

215-216 79

238-239 80

221-222 81

amorphous

TABLE 21 Ex. Structural formula m.p. (° C.) 82

amorphous 83

amorphous 84

amorphous 85

amorphous

TABLE 22 Ex. Structural formula m.p. (° C.) 86

amorphous 87

196-197 88

259-261 89

230 (dec.) 90

170-172 91

248-251

TABLE 23 Ex. Structural formula m.p. (° C.) 92

230 (dec.) 93

168-171 94

230 (dec.) 95

230 (dec.) 96

236-238 97

230 (dec.)

TABLE 24 Ex. Structural formula m.p. (° C.) 98

230 (dec.) 99

175-178 100

222-224 101

230 (dec.) 102

240

TABLE 25 Ex. Structural formula m.p. (° C.) 103

amorphous 104

178-180 105

193-195 106

132-134 107

amorphous

TABLE 26 Ex. Structural formula m.p. (° C.) 108

amorphous 109

144-146 110

amorphous 111

amorphous 112

amorphous

TABLE 27 Ex. Structural formula m.p. (° C.) 113

amorphous 114

amorphous 115

184 (dec.) 116

amorphous 117

120 (dec.)

TABLE 28 Ex. Structural formula m.p. (° C.) 118

125-127 119

139-141 120

250 (dec.) 121

170-174 122

186-189

TABLE 29 Ex. Structural formula m.p. (° C.) 123

amorphous 124

amorphous 125

270 (dec.) 126

270 (dec.) 127

135-140

TABLE 30 Ex. Structural formula m.p. (° C.) 128

223-225 129

187-189 130

200-202 131

167-169 132

185-189

TABLE 31 Ex. Structural formula m.p. (° C.) 133

230 (dec.) 134

230 (dec.) 135

amorphous 136

amorphous

TABLE 32 Ex. Structural formula m.p. (° C.) 137

218-220 138

235-236 139

250 (dec.) 140

179-180

TABLE 33 Ex. Structural formula m.p. (° C.) 141

189-190 142

195-197 143

amorphous 144

amorphous

TABLE 34 Ex. Structural formula m.p. (° C.) 145

amorphous 146

228-230 147

amorphous 148

208-211

TABLE 35 m.p. Ex. Structural formula (° C.) 149

152-154 150

230 (dec.) 151

211-212

TABLE 36 Ex. Structural formula m.p. (° C.) 152

160-163 153

152-155 154

184-185

TABLE 37 Ex. Structural formula m.p. (° C.) 155

218-219 156

218-221 157

230-234

TABLE 38 m.p. Ex. Structural formula (° C.) 158

212-213 159

194-196 160

184-185

TABLE 39 Ex. Structural formula m.p. (° C.) 161

amorphous 162

210-211 163

169-171

TABLE 40 Ex. Structural formula m.p. (° C.) 164

158-160 165

171-172

TABLE 41 Ex. Structural formula m.p. (° C.) 166

183-184 167

196-198 168

143-149

TABLE 42 Ex. Structural formula m.p. (° C.) 169

132-137 170

104-107

TABLE 43 Ex. Structural formula m.p. (° C.) 171

111-114 172

170-171 173

215-218

TABLE 44 m.p. Ex. Structural formula (° C.) 174

125-130 175

148-150

TABLE 45 m.p Ex. Structural formula (° C.) 176

190-192 177

170-175

TABLE 46 m.p Ex. Structural formula (° C.) 178

195-198 179

134-140

TABLE 47 Ex. Structural formula m.p. (° C.) 180

227-230 181

 98-100

TABLE 48 Ex. Structural formula m.p. (° C.) 182

216-218 183

230 184

195-197 185

173-176

TABLE 49 Ex. Structural formula m.p. (° C.) 186

220 187

182-189 188

230 (dec.) 189

213-214

TABLE 50 Ex. Structural formula m.p. (° C.) 190

228-230 191

160-162 192

amorphous 193

amorphous

TABLE 51 Ex. Structural formula m.p. (° C.) 194

180-181 195

amorphous 196

194-196 197

amorphous 198

amorphous

TABLE 52 Ex. Structural formula m.p. (° C.) 199

amorphous 200

amorphous 201

amorphous 202

amorphous

TABLE 53 Ex. Structural formula m.p. (° C.) 203

amorphous 204

183 (dec.) 205

220 206

159-161 207

189-191 208

210-213

TABLE 54 Ex. Structural formula m.p. (° C.) 209

190-193 210

225-227 211

208-210 212

181-183 213

191-193 214

amorphous

TABLE 55 Ex. Structural formula m.p. (° C.) 215

155-158 216

230 217

188-190 218

185-191

TABLE 56 Ex. Structural formula m.p. (° C.) 219

amorphous 220

117-119 221

105-108 222

146-147

TABLE 57 Ex. Structural formula m.p. (° C.) 223

174-176 224

151-152 225

127-128 226

157-159

TABLE 58 Ex. Structural formula m.p. (° C.) 227

172-173 228

155-157 229

176-177 230

114-115

TABLE 59 Ex. Structural formula m.p. (° C.) 231

250 232

144-145 233

166-167 234

180-181 235

162

TABLE 60 Ex. Structural formula m.p. (° C.) 236

158-159 237

164-167 238

212-213 239

159-163 240

130-135

TABLE 61 Ex. Structural formula m.p. (° C.) 241

147-148 242

149-150 243

122-127 244

153-154

TABLE 62 Ex. Structural formula m.p. (° C.) 245

132-134 246

205 (dec.) 247

209 (dec.) 248

104-105 249

117-118

TABLE 63 Ex. Structural formula m.p. (° C.) 250

116-117 251

175 (dec.) 252

174 (dec.) 253

240 254

amorphous

TABLE 64 Ex. Structural formula m.p. (° C.) 255

167-170 256

168-170 257

130 (dec.) 258

234-236 259

231-233

TABLE 65 Ex. Structural formula m.p. (° C.) 260

220-223 261

159 (dec.) 262

239 (dec.) 263

260 264

182-183

TABLE 66 m.p. Ex. Structural formula (° C.) 265

208-221 266

200-202 267

122-123 268

88-90 269

 99-101

TABLE 67 m.p. Ex. Structural formula (° C.) 270

100-104 271

76-84 272

75-79 273

87-92 274

230 (dec.)

A Formulation Example is shown in the following, which is not to beconstrued as limitative.

FORMULATION EXAMPLE

(a) Compound of Example 1 10 g (b) Lactose 50 g (c) Corn starch 15 g (d)Sodium carboxymethyl cellulose 44 g (e) Magnesium stearate  1 g

The total amount of (a), (b) and (c) and 30 g of (d) were kneaded withwater, dried in vacuo and granulated. The granulated powder was mixedwith 14 g of (d) and 1 g of (e) and the mixture was punched with atableting machine to give 1000 tablets containing 10 mg of (a) pertablet.

The test results of the protein tyrosine phosphatase 1B inhibitoryaction of the present invention are shown in the following.

EXPERIMENTAL EXAMPLE Experimental Example 1 Protein Tyrosine Phosphatase1B Inhibitory Action

Preparation of Assay Buffer:

50 mM Tris-HCl buffer (pH 7.5), and 50 mM NaCl and 3 mM dithiothreitol(DTT) were prepared.

Preparation of Sample:

Respective 10 mM DMSO solutions of 0.1, 0.3, 1, 3 and 10 μM testcompounds were diluted with the above-mentioned assay buffer so that thefinal dimethyl sulfoxide (DMSO) concentration would be not more than 1%.As a control, an assay buffer was used.

Preparation of Substrate:

A synthetic peptide consisting of 12 amino acids corresponding to1142nd-1153rd of insulin receptor sequence, wherein three tyrosinestherein had been phosphorylated, was diluted with the above-mentionedassay buffer to 80 μM.

Preparation of Enzyme:

A recombinant human protein tyrosine phosphatase 1B (manufactured byUBI) was diluted with the above-mentioned assay buffer (1.2 ng/25 μl).

(Evaluation Method)

A sample (10 μl) and a substrate (25 μl) prepared as mentioned abovewere successively added to a 96 well plate, and an enzyme (25 μl)prepared as mentioned above was added and mixed. After incubation atroom temperature for 60 min., malachite green (120 μl, Biomol), which isa phosphorus color fixing agent, was added, and the mixture was furtherincubated at room temperature for 20 min. to allow color development.The absorbance at 650 nm was measured on a plate reader, and the proteintyrosine phosphatase 1B inhibitory action of the test compound wasevaluated. The results are shown in Table 68.

Experimental Example 2 Hypoglycemic Action

A 0.5% methyl cellulose suspension of the test compound was orallyadministered to male ob/ob mice (6 to 9 weeks old) grouped based onblood glucose level. A 0.5% methyl cellulose solution alone wasadministered to a control group.

The blood was drawn from the orbital vein with anesthesia at 3 hoursafter the administration. The blood was drawn under fasting by removingthe feed immediately before test compound administration. The blood thusdrawn was separated by centrifugation and the blood glucose level wasmeasured from the obtained plasma according to the hexokinase method(glucose measure kit). For evaluation, decrease in the blood glucoselevel of the test compound administration group relative to the controlgroup was shown in percentage. The results are shown in Table 68. TABLE68 Decrease in blood glucose PTP1B inhibitory level (%) Example action(IC₅₀:μM) Dose (mg/kg) 3 hr 1 0.32 0.3 35 1 35 3 35 2 0.22 1 37 3 47 30.50 1 27 3 35 115 0.48 3 34 196 0.83 3 −8 208 0.11 3 21 209 0.49 3 20215 0.11 0.3 −9 1 32 3 39 217 0.26 3 20 218 0.15 3 27 230 0.15 3 40

Experimental Example 3 Blood Lipid Lowering Action

A 0.5% methyl cellulose suspension of the test compound was orallyadministered to 7-week-old db/db mice once a day for 14 days. The 0.5%methyl cellulose solution alone was administered to the control group.

The blood was drawn from the orbital vein with light ether anesthesiabefore test compound administration on day 7 day 14 under non-fastingcondition. The blood thus drawn was separated by centrifugation and theplasma triglyceride concentration was measured from the obtained plasmaaccording to the enzyme method (triglyceride measure kit). The resultsare shown in Table 69. TABLE 69 Plasma triglyceride Dose concentration(mg/dL) (mg/kg) Day 7 Day 14 Control group — 508 622 test compound 10277 349 administration 30 250 307 group (Example 102)

INDUSTRIAL APPLICABILITY

From the foregoing test results and the like, the compound [I] of thepresent invention is suggested have a superior PTP1B inhibitory action.That is, the compound [I] of the present invention is expected to be anew type of drug for the prophylaxis or treatment of diabetes that candirectly improve the insulin action, insulin sensitivity, insulinresistance and/or glucose resistance. In addition, the compound [I] ofthe present invention is also expected as a drug for the prophylaxis ortreatment of diabetic complications (retinopathy, nephropathy,neuropathy, cardiac infarction and cerebral infarction based onarteriosclerosis etc.), and further as a treatment drug of a diseasemediated by PTP1B. Moreover, because compound [I] of the presentinvention has been confirmed to show a blood lipid lowering action fromthe above test results, it is also expected as a drug for theprophylaxis or treatment of hyperlipidemia.

This application is based on a patent application No. 368567/2001 filedin Japan, the contents of which are hereby incorporated by reference.

1. An azole compound represented by the formula [I]

wherein W is a sulfur atom or an oxygen atom; R is (1) —COOR⁷ wherein R⁷is a hydrogen atom or a lower alkyl group), (2) —X¹-A¹-COOR⁷ wherein X¹is —O—, —N(R¹⁵)— or —S(O)_(p)— wherein R¹⁵ is a hydrogen atom or a loweralkyl group, p is 0, 1 or 2, A¹ is a lower alkylene group, and R⁷ is ahydrogen atom or a lower alkyl group, or (3) a tetrazolyl group; R¹, R²,R³ and R⁴ are each independently (1) a hydrogen atom, (2) a halogenatom, (3) a hydroxyl group, (4) an optionally substituted lowercycloalkylalkyloxy group, (5) an optionally substituted aralkyloxygroup, (6) a cyano group, (7) a nitro group, (8) a lower alkyl group,(9) a lower haloalkyl group, (10) a lower alkoxy group or (11) a lowerhaloalkoxy group; A is a group represented by —(CH₂)_(m)—X— wherein X is—N(R⁸)—, —C(R⁹)(R¹⁰)—, —CO— or —CO—N(R⁸)— wherein R⁸ is a hydrogen atom,—SO₂R¹⁶ (R¹⁶ is a lower alkyl group or an aryl group) or a lower alkylgroup, wherein said lower alkyl group is optionally substituted by asubstituent selected from the group consisting of a lower alkoxy group,an aryloxy group, —N(R¹¹)(R¹²) (R¹¹ and R¹² are each independently ahydrogen atom or a lower alkyl group or may form, together with anitrogen atom bonded thereto, a 5- to 7-membered hetero ring optionallyfurther having at least one hetero atom selected from the groupconsisting of nitrogen atom, oxygen atom and sulfur atom), a carboxygroup, a lower cycloalkyl group and an optionally substituted arylgroup, and R⁹ and R¹⁰ are each independently a hydrogen atom or a loweralkyl group or may form lower cycloalkane together with a carbon atombonded thereto, or may form, together with a carbon atom bonded thereto,a 5- to 7-membered hetero ring optionally further having at least onehetero atom selected from the group consisting of nitrogen atom, oxygenatom and sulfur atom, and m is 0 or an integer of 1 to 3; B is an arylgroup or an aromatic heterocyclic group; R⁵ is (1) a hydrogen atom, (2)a halogen atom, (3) a lower alkyl group, (4) a lower alkoxy group, (5) acyano group, (6) a nitro group, (7) a lower haloalkyl group or (8)—S(O)_(r)—R¹⁷ (R¹⁷ is a lower alkyl group or an aryl group and r is 0, 1or 2); and R⁶ is —(Y)_(s1)-(A²)_(s)-Z wherein s1 and s are eachindependently 0 or 1, Y is —O—, —S(O)_(t)—, —N(R¹³)—, —N(R¹⁴)—CO—,—N(R¹⁴)—SO₂—, —SO₂—N(R¹⁴)—, —C(R¹⁸)(R¹⁹)— or —CO— (wherein t is 0, 1 or2, R¹³ is (1) a hydrogen atom, (2) a lower alkyl group (wherein saidlower alkyl group optionally substituted by a substituent selected fromthe group consisting of (a) a lower cycloalkyl group, (b) an optionallysubstituted aryl group, (c) an optionally substituted heterocyclic groupand (d) a hydroxyl group), (3) a lower alkenyl group, (4) a loweralkylsulfonyl group or (5) a lower alkylcarbonyl group (wherein saidlower alkylcarbonyl group is optionally substituted by a hydroxyl groupor a lower alkoxy group), R¹⁴ is a hydrogen atom or a lower alkyl group,and R¹⁸ and R¹⁹ are each independently a hydrogen atom or a lower alkylgroup or may form lower cycloalkane together with a carbon atom bondedthereto, or may form, together with a carbon atom bonded thereto, a 5-to 7-membered hetero ring optionally further having at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atomand sulfur atom), A² is a lower alkylene group optionally substituted bya lower cycloalkyl group, and Z is (1) a lower cycloalkyl group (whereinsaid a lower cycloalkyl group is optionally substituted by an optionallysubstituted phenyl group), (2) an aryl group (wherein said aryl group isoptionally substituted by a substituent selected from the groupconsisting of (a) a heterocyclic group optionally substituted by asubstituent selected from the group consisting of a lower alkyl groupand a lower alkylcarbonyl group, (b) a lower cycloalkyl group optionallysubstituted by a substituent selected from the group consisting of ahydroxyl group, an oxo group, a halogen atom and a lower alkyl group,(c) a carboxy group, (d) a halogen atom, (e) an alkyl group, (f) a lowerhaloalkyl group, (g) a lower alkylamino group, (h) a di(loweralkyl)amino group, (i) a lower alkylthio group and (j) a lower alkoxygroup), (3) an optionally substituted aromatic heterocyclic group, (4)an indanyl group or (5) a piperazinyl group (wherein said piperazinylgroup is optionally substituted by a substituent selected from the groupconsisting of (a) a phenyl group, (b) a phenyl lower alkyl group, (c) abenzoyl group optionally substituted by a halogen atom and (d) a phenyllower alkoxycarbonyl group), a prodrug thereof or a pharmaceuticallyacceptable salt thereof.
 2. The azole compound of claim 1, wherein, inthe formula [I], W is a sulfur atom or an oxygen atom; R is (1) —COOR⁷wherein R⁷ is a hydrogen atom or a C₁₋₄ alkyl group, (2) —X¹-A¹-COOR⁷wherein X¹ is —O—, —N(R¹⁵)— or —S(O)_(p)— wherein R¹⁵ is a hydrogen atomor a C₁₋₄ alkyl group and p is 0, 1 or 2, A¹ is a C₁₋₄ alkylene group,R⁷ is a hydrogen atom or a C₁₋₄ alkyl group or (3) a tetrazolyl group,R¹, R², R³ and R⁴ are each independently, (1) a hydrogen atom, (2) ahalogen atom, (3) a hydroxyl group, (4) an optionally substitutedC₃₋₇cycloalkyl C₁₋₄ alkyloxy group, (5) an optionally substitutedaralkyloxy group, (6) a cyano group, (7) a nitro group, (8) a C₁₋₄ alkylgroup, (9) a C₁₋₄ haloalkyl group, (10) a C₁₋₄ alkoxy group or (11) aC₁₋₄ haloalkoxy group; A is a group represented by —(CH₂)_(m)—X— whereinX is —N(R⁸)—, —C(R⁹)(R¹⁰)—, —CO— or —CO—N(R⁸)— wherein R⁸ is a hydrogenatom, —SO₂R¹⁶ (R¹⁶ is a C₁₋₆ alkyl group or an aryl group) or a C₁₋₆alkyl group, wherein said C₁₋₆ alkyl group is optionally substituted bya substituent selected from the group consisting of a C₁₋₄ alkoxy group,an aryloxy group, —N(R¹¹)(R¹²) (R¹¹ and R¹² are each independently ahydrogen atom or a C₁₋₄ alkyl group or may form, together with anitrogen atom bonded thereto, a 5- to 7-membered hetero ring optionallyfurther having at least one hetero atom selected from the groupconsisting of nitrogen atom, oxygen atom and sulfur atom), a carboxygroup, C₃₋₇cycloalkyl group and an optionally substituted aryl group, R⁹and R¹⁰ are each independently a hydrogen atom or a C₁₋₄ alkyl group, ormay form a C₃₋₇ cycloalkane together with a carbon atom bonded thereto,or may form, together with a carbon atom bonded thereto, a 5- to7-membered hetero ring optionally further having at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atomand sulfur atom, m is 0 or an integer of 1 to 3; B is an aryl group oran aromatic heterocyclic group; R⁵ is (1) a hydrogen atom, (2) a halogenatom, (3) a C₁₋₄ alkyl group, (4) a C₁₋₄ alkoxy group, (5) a cyanogroup, (6) a nitro group, (7) a C₁₋₄ haloalkyl group or (8)—S(O)_(r)—R¹7 (R¹⁷ is a C₁₋₆ alkyl group or an aryl group and r is 0, 1or 2); R⁶ is —(Y)_(s1)-(A²)_(s)-Z wherein s1 and s are eachindependently 0 or 1, Y is —O—, —S(O)_(t)—, —N(R¹³)—, —N(R¹⁴)—CO—,—N(R¹⁴)—SO₂—, —SO₂—N(R¹⁴)—, —C(R¹8)(R¹⁹)— or —CO— (wherein t is 0, 1 or2, R¹³ is (1) a hydrogen atom, (2) a C-4 alkyl group (wherein said C₁₋₄alkyl group is optionally substituted by a substituent selected from thegroup consisting of (a) a C₃₋₇ cycloalkyl group, (b) an optionallysubstituted aryl group, (c) an optionally substituted heterocyclic groupand (d) a hydroxyl group), (3) a C₂₋₄ alkenyl group, (4) a C₁₋₄alkylsulfonyl group or (5) a C₁₋₄ alkylcarbonyl group (wherein said C₁₋₄alkylcarbonyl group is optionally substituted by a hydroxyl group or aC₁₋₄ alkoxy group), R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group, R¹⁸and R¹⁹ are each independently a hydrogen atom or a C₁₋₄ alkyl group, ormay form C₃₋₇ cycloalkane together with a carbon atom bonded thereto, ormay form, together with a carbon atom bonded thereto, a 5- to 7-memberedhetero ring optionally further having at least one hetero atom selectedfrom the group consisting of nitrogen atom, oxygen atom and sulfuratom), A² is a C₁₋₄ alkylene group optionally substituted by a C₃₋₇cycloalkyl group, Z is (1) a C₃₋₇cycloalkyl group (wherein said C₃₋₇cycloalkyl group is optionally substituted by a phenyl group optionallysubstituted by a halogen atom), (2) an aryl group (wherein said arylgroup is optionally substituted by a substituent selected from the groupconsisting of (a) a heterocyclic group optionally substituted by asubstituent selected from the group consisting of a C₁₋₄ alkyl group anda C₁₋₄ alkylcarbonyl group, (b) a C₃₋₇ cycloalkyl group optionallysubstituted by a substituent selected from the group consisting of ahydroxyl group, an oxo group, a halogen atom and a C₁₋₄ alkyl group, (c)a carboxy group, (d) a halogen atom, (e) a C₁₋₈ alkyl group, (f) a C₁₋₄haloalkyl group, (g) a C₁₋₄ alkylamino group, (h) a di(C₁₋₄ alkyl)aminogroup, (i) a C₁₋₄ alkylthio group and (j) a C₁₋₄ alkoxy group), (3) anaromatic heterocyclic group (wherein said aromatic heterocyclic group isoptionally substituted by a substituent selected from the groupconsisting of (a) a heterocyclic group optionally substituted by a C₁₋₄alkyl group, (b) a C₁₋₆ alkyl group, (c) an aryl group optionallysubstituted by a halogen atom or a C₁₋₄ haloalkyl group, (d) a halogenatom, (e) a C₁₋₄ haloalkyl group, (f) a carboxy group, (g) a C₃₋₇cycloalkyl group and (h) a C₁₋₄ alkoxy group), (4) an indanyl group or(5) a piperazinyl group (wherein said piperazinyl group is optionallysubstituted by a substituent selected from the group consisting of (a) aphenyl group, (b) a phenyl C₁₋₄ alkyl group, (c) a benzoyl groupoptionally substituted by a halogen atom and (d) a phenyl C₁₋₄alkoxycarbonyl group), a prodrug thereof or a pharmaceuticallyacceptable salt thereof.
 3. The azole compound of claim 2, wherein W isa sulfur atom or an oxygen atom, R is (1) —COOR⁷ wherein R⁷ is ahydrogen atom, (2) —X¹-A¹-COOR⁷ wherein X¹ is —O—, A¹ is a C₁₋₄ alkylenegroup, R⁷ is a hydrogen atom or (3) a tetrazolyl group; R¹, R², R³ andR⁴ are each independently (1) a hydrogen atom, (2) a halogen atom, (3) ahydroxyl group, (4) an optionally substituted C₃₋₇ cycloalkyl C₁₋₄alkyloxy group or (5) an optionally substituted aralkyloxy group; A is agroup represented by —(CH₂)_(m)—X— wherein X is —N(R⁸)—, —C(R⁹)(R¹⁰)— or—CO— wherein R⁸ is a hydrogen atom or a C₁₋₆ alkyl group, wherein saidC₁₋₆ alkyl group is optionally substituted by a substituent selectedfrom the group consisting of a C₁₋₄ alkoxy group, an aryloxy group,—N(R¹¹)(R¹²) (R¹¹ and R¹² are each independently a hydrogen atom or aC₁₋₄ alkyl group or may form, together with a nitrogen atom bondedthereto, a 5- to 7-membered hetero ring optionally further having atleast one hetero atom selected from the group consisting of nitrogenatom, oxygen atom and sulfur atom), a carboxy group, a C₃₋₇ cycloalkylgroup and an optionally substituted aryl group, R⁹ and R¹⁰ are eachindependently a hydrogen atom or a C₁₋₄ alkyl group, or may form C₃₋₇cycloalkane together with a carbon atom bonded thereto, or may form,together with a carbon atom bonded thereto, a 5- to 7-membered heteroring optionally further having at least one hetero atom selected fromthe group consisting of nitrogen atom, oxygen atom and sulfur atom, m is0 or an integer of 1 to 3; B is an aryl group or an aromaticheterocyclic group; R⁵ is (1) a hydrogen atom, (2) a halogen atom, (3) aC₁₋₄ alkyl group or (4) a C₁₋₄ alkoxy group; R⁶ is —(Y)_(s1)-(A²)_(s)-Zwherein s1 and s are each independently 0 or 1, Y is —O—, —S(O)_(t)—,—N(R¹³)—, —N(R¹⁴)—CO— or —N(R¹⁴)—SO₂— wherein t is 0, 1 or 2, R¹³ is (1)a hydrogen atom, (2) a C-4 alkyl group (wherein said C₁₋₄ alkyl group isoptionally substituted by a substituent selected from the groupconsisting of (a) a C₃₋₇cycloalkyl group, (b) an optionally substitutedaryl group, (c) an optionally substituted heterocyclic group and (d) ahydroxyl group), (3) a C₂₋₄ alkenyl group, (4) a C₁₋₄ alkylsulfonylgroup or (5) a C₁₋₄ alkylcarbonyl group (wherein said C₁₋₄ alkylcarbonylgroup is optionally substituted by a hydroxyl group or a C₁₋₄ alkoxygroup), R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group, A² is a C₁₋₄alkylene group optionally substituted by a C₃₋₇ cycloalkyl group, Z is(1) a C₃₋₇cycloalkyl group (wherein said C₃₋₇ cycloalkyl group isoptionally substituted by a phenyl group), (2) an aryl group (whereinsaid aryl group is optionally substituted by a substituent selected fromthe group consisting of (a) a heterocyclic group optionally substitutedby a C₁₋₄ alkyl group or a C₁₋₄ alkylcarbonyl group, (b) a C₃₋₇cycloalkyl group optionally substituted by a substituent selected fromthe group consisting of a hydroxyl group, an oxo group, a halogen atomand a C-4 alkyl group, (c) a carboxy group, (d) a halogen atom, (e) aC₁₋₈ alkyl group, (f) a C₁₋₄ haloalkyl group, (g) a C₁₋₄ alkylaminogroup and (h) a di(C₁₋₄ alkyl)amino group, (i) a C₁₋₄ alkylthio groupand (j) a C₁₋₄ alkoxy group), (3) an aromatic heterocyclic group(wherein said aromatic heterocyclic group is optionally substituted by asubstituent selected from the group consisting of (a) a heterocyclicgroup, (b) a C₁₋₄ alkyl group and (c) a phenyl group optionallysubstituted by a halogen atom or a C₁₋₄ haloalkyl group), (4) an indanylgroup or (5) a piperazinyl group (wherein said piperazinyl group isoptionally substituted by a substituent selected from the groupconsisting of (a) a phenyl group, (b) a phenyl C₁₋₄ alkyl group and (c)a phenyl C₁₋₄ alkoxycarbonyl group), a prodrug thereof or apharmaceutically acceptable salt thereof.
 4. The azole compound of claim3, wherein W is a sulfur atom and m is 0 or 1, a prodrug thereof or apharmaceutically acceptable salt thereof.
 5. The azole compound of claim4, wherein A is —(CH₂)_(m)—X— wherein X is —N(R⁸)— wherein R⁸ is ahydrogen atom or a C₁₋₆ alkyl group, wherein said C₁₋₆ alkyl group isoptionally substituted by a substituent selected from the groupconsisting of a C₁₋₄ alkoxy group, an aryloxy group, —N(R¹¹)(R¹²) (R¹¹and R¹² are each independently a hydrogen atom or a C₁₋₄ alkyl group ormay form, together with a nitrogen atom bonded thereto, a 5- to7-membered hetero ring optionally further having at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atomand sulfur atom), a carboxy group, a C₃₋₇ cycloalkyl group and anoptionally substituted aryl group, and m is 0 or 1, a prodrug thereof ora pharmaceutically acceptable salt thereof.
 6. The azole compound ofclaim 5, wherein R is —X¹-A¹-COOR⁷ wherein each symbol is as defined inclaim 3, a prodrug thereof or a pharmaceutically acceptable saltthereof.
 7. The azole compound of claim 5, wherein R is —COOR⁷ whereinR⁷ is a hydrogen atom, a prodrug thereof or a pharmaceuticallyacceptable salt thereof.
 8. The azole compound of claim 7, wherein R¹,R², R³ and R⁴ are hydrogen atoms, a prodrug thereof or apharmaceutically acceptable salt thereof.
 9. The azole compound of claim8, wherein B is a phenyl group, a thiazolyl group, a pyridyl group, abenzothiazolyl group, a benzoimidazolyl group or a benzoxazolyl group, aprodrug thereof or a pharmaceutically acceptable salt thereof.
 10. Theazole compound of claim 9, wherein B is a phenyl group, a prodrugthereof or a pharmaceutically acceptable salt thereof.
 11. The azolecompound of claim 10, wherein R⁵ is a hydrogen atom, a prodrug thereofor a pharmaceutically acceptable salt thereof.
 12. The azole compound ofclaim 11, wherein, for R⁶, Z is (1) a C₃₋₇cycloalkyl group (wherein saidC₃₋₇cycloalkyl group is optionally substituted by a phenyl group), (2)an aryl group (wherein said aryl group is optionally substituted by asubstituent selected from the group consisting of (a) a heterocyclicgroup optionally substituted by a C₁₋₄ alkyl group or a C₁₋₄alkylcarbonyl group, (b) a C₃₋₇ cycloalkyl group optionally substitutedby a substituent selected from the group consisting of a hydroxyl group,an oxo group, a halogen atom and a C₁₋₄ alkyl group, (c) a carboxygroup, (d) a halogen atom, (e) a C₁₋₈ alkyl group, (f) a C₁₋₄ haloalkylgroup, (g) a C₁₋₄ alkylamino group, (h) a di(C₁₋₄ alkyl)amino group, (i)a C₁₋₄ alkylthio group and (j) a C₁₋₄ alkoxy group) or (3) an aromaticheterocyclic group (wherein said aromatic heterocyclic group isoptionally substituted by a substituent selected from the groupconsisting of (a) a heterocyclic group, (b) a C₁₋₄ alkyl group and (c) aphenyl group optionally substituted by a halogen atom or a C₁₋₄haloalkyl group), a prodrug thereof or a pharmaceutically acceptablesalt thereof.
 13. The azole compound of claim 12, wherein Z is an arylgroup optionally substituted by a substituent selected from the groupconsisting of (a) a heterocyclic group optionally substituted by a C₁₋₄alkyl group or a C₁₋₄ alkylcarbonyl group, (b) a C₃₋₇ cycloalkyl groupoptionally substituted by a substituent selected from the groupconsisting of a hydroxyl group, an oxo group, a halogen atom and a C₁₋₄alkyl group, (c) a carboxy group, (d) a halogen atom, (e) a C₁₋₈ alkylgroup, (f) a C₁₋₄ haloalkyl group, (g) a C₁₋₄ alkylamino group, (h) adi(C₁₋₄ alkyl)amino group, (i) a C₁₋₄ alkylthio group and (j) a C₁₋₄alkoxy group, a prodrug thereof or a pharmaceutically acceptable saltthereof.
 14. The azole compound of claim 13, wherein Z is a phenyl groupsubstituted by a substituent selected from the group consisting of (a) acyclohexyl group or a cyclopentyl group optionally substituted by asubstituent selected from the group consisting of a hydroxyl group, anoxo group, a halogen atom and a C₁₋₄ alkyl group, (b) a heterocyclicgroup optionally substituted by a C₁₋₄ alkyl group or a C₁₋₄alkylcarbonyl group (wherein said heterocyclic group is selected fromthe group consisting of a piperidinyl group, a morpholinyl group, apiperazinyl group, a tetrahydropyranyl group, a pyrrolidinyl group and apyrrolyl group) and (c) a C₁₋₈ alkyl group, a prodrug thereof or apharmaceutically acceptable salt thereof.
 15. The azole compound ofclaim 14, wherein Z is a phenyl group substituted by a cyclohexyl groupoptionally substituted by a substituent selected from the groupconsisting of a hydroxyl group, an oxo group, a halogen atom and a C₁₋₄alkyl group, a prodrug thereof or a pharmaceutically acceptable saltthereof.
 16. The azole compound of claim 13 or claim 11 wherein, forR¹⁶, Y is —O—, —N(R¹³)— or —N(R¹⁴)—CO— wherein R¹³ is a hydrogen atom, aC₁₋₄ alkyl group or a C₂₋₄ alkenyl group, wherein said C₁₋₄ alkyl groupis optionally substituted by a substituent selected from the groupconsisting of a C₃₋₇ cycloalkyl group, an optionally substituted arylgroup, an optionally substituted heterocyclic group and a hydroxylgroup, R¹⁴ is a hydrogen atom or a C₁₋₄ alkyl group, and s1 is 1, aprodrug thereof or a pharmaceutically acceptable salt thereof.
 17. Theazole compound of claim 16, wherein, for R⁶, A² is a methylene group, aprodrug thereof or a pharmaceutically acceptable salt thereof.
 18. Apharmaceutical composition comprising an azole compound of claim 1, aprodrug thereof or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 19. A pharmaceutical compositionfor inhibiting protein Tyrosine Phosphatase 1B, which comprises an azolecompound of claim 1, a prodrug thereof or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 20. Apharmaceutical composition for treating diabetes, which comprises anazole compound of claim 1, a prodrug thereof or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 21.A pharmaceutical composition for treating hyperlipidemia, whichcomprises an azole compound of claim 1, a prodrug thereof or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 22. The pharmaceutical composition of claim 18,which is used in combination with a different therapeutic drug forhyperlipidemia.
 23. The pharmaceutical composition of claim 22, whereinthe therapeutic drug for hyperlipidemia is a statin pharmaceuticalagent.
 24. The pharmaceutical composition of claim 23, wherein thestatin pharmaceutical agent is selected from the group consisting oflovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin andcerivastatin.
 25. The pharmaceutical composition of claim 18, which isused in combination with a different therapeutic drug for diabetes. 26.The pharmaceutical composition of claim 25, which is used in combinationwith a therapeutic agent for diabetes selected from the group consistingof an insulin secretagogue, a sulfonylurea, a sulfonamide, a biguanide,an α glucosidase inhibitor, an insulin preparation and an insulinsensitizer.
 27. The pharmaceutical composition of claim 26, wherein thetherapeutic agent for diabetes is selected from the group consisting ofnateglide, glimepiride, glibenclamide, gliclazide, acetohexamide,tolbutamide, glyclopyramide, tolazamide, glybuzole, metforminhydrochloride, buformin hydrochloride, voglibose, acarbose, insulin andpioglitazone hydrochloride.
 28. The pharmaceutical composition of claim20, which is used in combination with a different therapeutic drug forhyperlipidemia.
 29. The pharmaceutical composition of claim 28, whereinthe therapeutic drug for hyperlipidemia is a statin pharmaceuticalagent.
 30. The pharmaceutical composition of claim 29, wherein thestatin pharmaceutical agent is selected from the group consisting oflovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin andcerivastatin.
 31. The pharmaceutical composition of claim 20, which isused in combination with a different therapeutic drug for diabetes. 32.The pharmaceutical composition of claim 31, which is used in combinationwith a therapeutic drug for diabetes selected from the group consistingof an insulin secretagogue, a sulfonylurea, a sulfonamide, a biguanide,an α glucosidase inhibitor, an insulin preparation and an insulinsensitizer.
 33. The pharmaceutical composition of claim 32, wherein thetherapeutic agent for diabetes is selected from the group consisting ofnateglide, glimepiride, glibenclamide, gliclazide, acetohexamide,tolbutamide, glyclopyramide, tolazamide, glybuzole, metforminhydrochloride, buformin hydrochloride, voglibose, acarbose, insulin andpioglitazone hydrochloride.
 34. The pharmaceutical composition of claim21, which is used in combination with a different therapeutic drug forhyperlipidemia.
 35. The pharmaceutical composition of claim 34, whereinthe therapeutic drug for hyperlipidemia is a statin pharmaceuticalagent.
 36. The pharmaceutical composition of claim 35, wherein thestatin pharmaceutical agent is selected from the group consisting oflovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin andcerivastatin.
 37. The pharmaceutical composition of claim 21, which isused in combination with a different therapeutic drug for diabetes. 38.The pharmaceutical composition of claim 37, which is used in combinationwith a therapeutic drug for diabetes selected from the group consistingof an insulin secretagogue, a sulfonylurea, a sulfonamide, a biguanide,an α glucosidase inhibitor, an insulin preparation and an insulinsensitizer.
 39. The pharmaceutical composition of claim 38, wherein thetherapeutic agent for diabetes is selected from the group consisting ofnateglide, glimepiride, glibenclamide, gliclazide, acetohexamide,tolbutamide, glyclopyramide, tolazamide, glybuzole, metforminhydrochloride, buformin hydrochloride, voglibose, acarbose, insulin andpioglitazone hydrochloride.
 40. A method of inhibiting protein TyrosinePhosphatase 1B, which comprises administering an effective amount of anazole compound of claim 1, a prodrug thereof or a pharmaceuticallyacceptable salt thereof to a mammal.
 41. A method of treating diabetes,which comprises administering an effective amount of an azole compoundof claim 1, a prodrug thereof or a pharmaceutically acceptable saltthereof to a mammal.
 42. A method of treating hyperlipidemia, whichcomprises administering an effective amount of an azole compound ofclaim 1, a prodrug thereof or a pharmaceutically acceptable salt thereofto a mammal.
 43. Use of an azole compound of claim 1, a prodrug thereofor a pharmaceutically acceptable salt thereof for the production of aprotein tyrosine phosphatase 1B inhibitor.
 44. Use of an azole compoundof claim 1, a prodrug thereof or a pharmaceutically acceptable saltthereof for the production of a therapeutic agent for diabetes.
 45. Useof an azole compound of claim 1, a prodrug thereof or a pharmaceuticallyacceptable salt thereof for the production of a therapeutic agent forhyperlipidemia.
 46. A commercial package comprising the pharmaceuticalcomposition of claim 18 and a written matter associated therewith, thewritten matter stating that said pharmaceutical composition can orshould be used for inhibiting protein Tyrosine Phosphatase 1B.
 47. Acommercial package comprising the pharmaceutical composition of claim 18and a written matter associated therewith, the written matter statingthat said pharmaceutical composition can or should be used for treatingdiabetes.
 48. A commercial package comprising the pharmaceuticalcomposition of claim 18 and a written matter associated therewith, thewritten matter stating that said pharmaceutical composition can orshould be used for treating hyperlipidemia.
 49. A method of treatinghyperlipidemia, which comprises administering an effective amount of anazole compound of claim 1, a prodrug thereof or a pharmaceuticallyacceptable salt thereof to a mammal, and administering an effectiveamount of a different therapeutic drug for hyperlipidemia to saidmammal.
 50. The method of treating of claim 49, wherein the therapeuticdrug for hyperlipidemia is a statin pharmaceutical agent.
 51. The methodof treating of claim 50, wherein the statin pharmaceutical agent isselected from the group consisting of lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin and cerivastatin.
 52. A method oftreating diabetes, which comprises administering an effective amount ofan azole compound of claim 1, a prodrug thereof or a pharmaceuticallyacceptable salt thereof to a mammal, and administering an effectiveamount of a different therapeutic agent for diabetes to said mammal. 53.The method of treating of claim 52, wherein the therapeutic agent fordiabetes is selected from the group consisting of an insulinsecretagogue, a sulfonylurea, a sulfonamide, a biguanide, an αglucosidase inhibitor, an insulin preparation and an insulin sensitizer.54. The method of treating of claim 53, wherein the therapeutic agentfor diabetes is selected from the group consisting of nateglide,glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide,glyclopyramide, tolazamide, glybuzole, metformin hydrochloride, buforminhydrochloride, voglibose, acarbose, insulin and pioglitazonehydrochloride.